EP4405477A1 - Compounds targeting nrl for the treatment of retinitis pigmentosa - Google Patents

Compounds targeting nrl for the treatment of retinitis pigmentosa

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Publication number
EP4405477A1
EP4405477A1 EP22873810.0A EP22873810A EP4405477A1 EP 4405477 A1 EP4405477 A1 EP 4405477A1 EP 22873810 A EP22873810 A EP 22873810A EP 4405477 A1 EP4405477 A1 EP 4405477A1
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EP
European Patent Office
Prior art keywords
nucleotides
independently
unsubstituted
substituted
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22873810.0A
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German (de)
French (fr)
Inventor
Charles Allerson
Arthur T. Suckow
Jill Magnus
Bryan Laffitte
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Novartis AG
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Novartis AG
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Publication of EP4405477A1 publication Critical patent/EP4405477A1/en
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/32—Special delivery means, e.g. tissue-specific

Definitions

  • BACKGROUND Retinitis pigmentosa is a hereditary retinal degenerative disease characterized by the loss of photoreceptors, leading to severe visual impairment and eventually complete blindness.
  • Photoreceptors are specialized neuronal cells in the retina that capture light and convert it to electrical signals in the process known as phototransduction.
  • the two types of photoreceptors are rods and cones. Rods are stimulated by dim light and responsible for vision in dark conditions. Cones are stimulated by bright light and responsible for color vision and vision in light conditions.
  • RP typically involves degeneration of rods, followed by a loss of cones.
  • RP typically presents with night blindness (nyctalopia).
  • RP has been linked to over 3,000 mutations in approximately 60 genes, most of which are critical for rod development and function (Hartong et al., 2006). These mutations may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.
  • Neural retina leucine zipper is a rod-specific transcription factor that is one of several transcription factors responsible for the regulation of photoreceptor gene expression.
  • nucleic acid compounds targeted to the NRL mRNA are provided herein.
  • a compound comprising an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein each of the antisense strand and sense strands is 15 to 25 nucleotides in length, the nucleotide sequence of the antisense strand is at least 90% complementary to the nucleotide sequence of the NRL mRNA (SEQ ID NO: 1), and the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 contiguous nucleotides of any one of nucleotides 501 to 563 of SEQ ID NO: 1, nucleotides 602 to 626 of SEQ ID NO: 1, nucleotides 623 to 654 of SEQ ID NO: 1, nucleotides 684 to 710 of SEQ ID NO: 1, nucleotides 741 to 765 of SEQ ID NO: 1, nucleotides 759 to 777 of SEQ ID NO: 1, nucleotides 882 to 909 of SEQ ID NO: 1, or nucleotides 1111 to 1133 of SEQ ID NO: 1, and the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand.
  • the antisense strand and the sense strand are not covalently linked.
  • at least one nucleotide of the antisense strand is a modified nucleotide.
  • at least one nucleotide of the sense strand is a modified nucleotide.
  • the antisense strand is 21 to 23 nucleotides in length.
  • the sense strand is 21 to 23 nucleotides in length.
  • the hybridization of the antisense strand to the sense strand forms at least one blunt end.
  • at least one strand comprises a 3’ nucleotide overhand of one to five nucleotides.
  • the compound comprises a ligand covalently linked to the antisense strand or the sense strand.
  • the compound has the structure: A is the sense strand or the antisense strand.
  • t is an integer from 1 to 5.
  • L 3 and L 4 are independently a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO 2 -O-, -O-P(O)(S)-O-, -O-P(O)(R 25 )-O-, -O-P(S)(R 25 )-O-, -
  • Each R 23 , R 24 and R 25 is independently hydrogen or unsubstituted C1-C10 alkyl.
  • L 5 is -L 5A -L 5B -L 5C -L 5D -L 5E -.
  • L 6 is -L 6A -L 6B -L 6C -L 6D -L 6E -.
  • L 5A , L 5B , L 5C , L 5D , L 5E , L 6A , L 6B , L 6C , L 6D , and L 6E are independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, –C(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; and each R 23 , R 24 and R 25 is independently hydrogen or unsubstituted C1-C10 alkyl.
  • R 1 and R 2 are independently unsubstituted C 1 -C 25 alkyl, wherein at least one of R 1 and R 2 is unsubstituted C9-C19 alkyl.
  • R 3 is hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, –N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • the compound is selected from DT-000429, DT-000430, DT- 000431, DT-000432, DT-000735, DT-000736, DT-000737, DT-000738, DT-000776, DT- 000777, DT-000778, DT-000785, DT-000786, DT-000787, DT-000828, DT-000829, DT- 000830, DT-000831, and DT-000832.
  • the compound is selected from DT- 001373, DT-001374, DT-001375, and DT-001386.
  • a pharmaceutical composition comprising the compound as described herein.
  • a method of inhibiting the expression of neural retina leucine zipper (NRL) in a subject comprising administering to the subject an effective amount the compound or pharmaceutical composition as described herein.
  • a method of treating retinitis pigmentosa comprising administering to a subject in need thereof an effective amount of the compound or pharmaceutical composition as described herein.
  • FIG.1A shows a representative image of H&E staining of the photoreceptor layer in the retina of a PBS-treated rd10 mouse.
  • FIG.1B shows a representative image of H&E staining of the photoreceptor layer in the retina of a DT-000239-treated rd10 mouse.
  • FIG.2A shows the scotopic wave measurements over time in the eyes of P23H RP mice following administration of PBS in the left eye and DT-000239 in the right eye.
  • FIG.2B shows the photopic wave measurements over time in the eyes of P23H RP mice following administration of PBS in the left eye and DT-000239 in the right eye.
  • FIG.3A shows a representative image of H&E staining of the photoreceptor layer in the retina of a PBS-treated P23H RP mouse.
  • FIG.3B shows a representative image of H&E staining of the photoreceptor layer in the retina of a DT-000239-treated P23H RP mouse.
  • FIG.4 shows the average percent NRL mRNA level over time following IVT injection of PBS, DT-000239, DT-000430, or DT-000432.
  • FIG.5A shows a representative image of H&E staining of the photoreceptor layer in the retina of a PBS-treated rd10 mouse.
  • FIG.5B shows a representative image of H&E staining of the photoreceptor layer in the retina of a DT-000430-treated rd10 mouse.
  • FIG.5C shows a representative image of H&E staining of the photoreceptor layer in the retina of a PBS-treated rd10 mouse.
  • FIG.5D shows a representative image of H&E staining of the photoreceptor layer in the retina of a DT-000432-treated rd10 mouse.
  • FIG.6A shows a representative image of H&E staining of the photoreceptor layer in the retina of a PBS-treated rd10 mouse.
  • FIG.6B shows a representative image of H&E staining of the photoreceptor layer in the retina of a DT-000430-treated rd10 mouse.
  • FIG.7A shows the amount of human NRL mRNA remaining following IVT injection of PBS or compound in humanized NRL mice.
  • FIG.7B shows the amount of mouse NRL mRNA remaining following IVT injection of PBS or compound in humanized NRL mice.
  • Retinitis pigmentosa is a hereditary retinal degenerative disease characterized by the loss of photoreceptors.
  • the terms are to be interpreted synonymously with the phrases “having at least” or “including at least.”
  • the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term “comprising” means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.
  • substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH 2 -.
  • RP Retinitis pigmentosa
  • RP means an inherited disease characterized by loss of photoreceptor function and eventual blindness. RP is caused by a mutation in one of various genes encoding proteins that participate in the visual cycle. Mutations that cause RP may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.
  • Compound means a molecule comprising linked monomeric nucleotides. A compound may have one or more modified nucleotides. In embodiments, a compound comprises a double-stranded nucleic acid. In embodiments, a compound comprises a single-stranded nucleic acid. A compound may be provided as a pharmaceutical salt. A compound may be provided as a pharmaceutical composition.
  • Oligonucleotide means a polymer of linked monomeric nucleotides. One or more nucleotides of an oligonucleotide may be a modified nucleotide.
  • Double-stranded nucleic acid means a first nucleotide sequence hybridized to a second nucleotide sequence to form a duplex structure. Double-stranded nucleic acids include structures formed from annealing a first oligonucleotide to a second, complementary oligonucleotide, as in an siRNA. Such double-stranded nucleic acids may have a short nucleotide overhang at one or both ends of the duplex structure.
  • Double-stranded nucleic acids also include structures formed from a single oligonucleotide with sufficient length and self-complementarity to form a duplex structure, as in an shRNA. Such double-stranded nucleic acids include stem-loop structures. A double-stranded nucleic acid may include one or more modifications relative to a naturally occurring terminus, sugar, nucleobase, and/or phosphate group. “Double-stranded region” means the portion of a double-stranded nucleic acid where nucleotides of the first nucleotide sequence are hybridized to nucleotides of the second nucleotide sequence.
  • a double-stranded region can be a defined portion within a double-stranded nucleic acid that is shorter than (e.g. encompassed by) the full double-stranded nucleic acid. Alternatively, a double-stranded region can be the same length as the full double-stranded nucleic acid. A double-stranded region may contain one or more mismatches between the first and second nucleotide sequences, and retain the ability hybridize with each other. Double-stranded regions do not include nucleotide overhangs. “Antisense strand” means an oligonucleotide that is complementary to a target RNA (e.g.
  • RNA-induced silencing complex RISC
  • the antisense strand may also be referred to as the “guide strand.”
  • Sense strand means an oligonucleotide that is complementary to the antisense strand of a double-stranded nucleic acid.
  • the sense strand is typically degraded following incorporation of the antisense strand into RISC.
  • the sense strand may also be referred to as the “passenger strand.”
  • Nucleotide overhang means an extension of one or more unpaired nucleotides from the double-stranded region of a double-stranded nucleic acid.
  • a nucleotide overhang can be one, two, three, four or five nucleotides.
  • One or more nucleotides of a nucleotide overhang may be a modified nucleotide.
  • a nucleotide overhang may be on the antisense strand, the sense strand, or both the antisense and sense strands.
  • “Blunt end” means a given terminus of a double-stranded nucleic acid with no unpaired nucleotides extending from the double-stranded region, i.e. there is no nucleotide overhang.
  • a double-stranded nucleic acid may have a blunt end at one or both termini.
  • siRNA means a double-stranded nucleic acid formed from separate antisense and sense strands, which directs gene silencing in a sequence-specific manner by facilitating mRNA degradation before translation through the RNA interference pathway. The antisense and sense strands of an siRNA are not covalently linked.
  • siRNA means a double-stranded nucleic acid containing a loop structure that is processed in a cell to an siRNA which directs gene silencing in a sequence-specific manner, by facilitating mRNA degradation before translation through the RNA interference pathway.
  • Single-stranded nucleic acid means an antisense strand that is not hybridized to a complementary strand.
  • a single-stranded nucleic acid is incorporated into RISC to direct gene silencing in a sequence-specific manner by facilitating mRNA degradation before translation through the RNA interference pathway.
  • Hybridize means the annealing of one nucleotide sequence to another nucleotide sequence based at least in part on nucleotide sequence complementarity.
  • an antisense strand is hybridized to a sense strand. In embodiments, an antisense strand hybridizes to a target mRNA sequence. “Complementary” means nucleobases having the capacity to pair non-covalently via hydrogen bonding. “Fully complementary” means each nucleobase of a first nucleotide sequence is complementary to each nucleobase of a second nucleotide sequence. In embodiments, an antisense strand is fully complementary to its target mRNA. In embodiments, a sense strand and an antisense strand of double-stranded nucleic acid are fully complementary over their entire lengths.
  • a sense strand and an antisense strand of double-stranded nucleic acid are fully complementary over the entire length of the double-stranded region of the siRNA, and one or both termini of either strand comprises single-stranded nucleotides.
  • "Identical" in the context of nucleotide sequences means having the same nucleotide sequence, independent of sugar, linkage, and/or nucleobase modifications and independent of the methylation state of any pyrimidines present.
  • Percent identity means the number of nucleobases in a first nucleotide sequence that are identical to nucleobases at corresponding positions in a second nucleotide sequence, divided by the total number of nucleobases in the first nucleotide sequence.
  • Mismatch means a nucleobase of a first nucleotide sequence that is not capable of Watson-Crick pairing with a nucleobase at a corresponding position of a second nucleotide sequence.
  • Nucleoside means a monomer of a nucleobase and a pentofuranosyl sugar (e.g., either ribose or deoxyribose).
  • Nucleosides may comprise bases such as A, C, G, T, or U, or modifications thereof. Nucleosides may be modified at the base and/or and the sugar. In embodiments, a nucleoside is a deoxyribonucleoside. In embodiments, the nucleoside is a ribonucleoside. “Nucleotide” means a nucleoside covalently linked to a phosphate group at the 5’ carbon of the pentafuranosyl sugar. Nucleotides may be modified at one or more of the nucleobase, sugar moiety, internucleotide linkage and/or phosphate group. “Nucleobase” means a heterocyclic base moiety capable of non-covalently pairing.
  • Nucleobases include pyrimidines and purines. Unless stated otherwise, numbering of nucleotide atoms is according to standard numbering convention, with the carbons of the pentafuranosyl sugar numbered 1’ through 5’, and the nucleobase atoms numbered 1 through 9 for purines and 1 through 6 for pyrimidines.
  • “Modified nucleoside” means a nucleoside having one or more modifications relative to a naturally occurring nucleoside. Such alterations may be present in a nucleobase and/or sugar moiety of the nucleoside. A modified nucleoside may have a modified sugar moiety and an unmodified nucleobase.
  • a modified nucleoside may have a modified sugar moiety and a modified nucleobase.
  • “Modified nucleotide” means a nucleotide having one or more alterations relative to a naturally occurring nucleotide. An alteration may be present in an internucleoside linkage, a nucleobase, and/or a sugar moiety of the nucleotide.
  • a modified nucleotide may have a modified sugar moiety and an unmodified phosphate group.
  • a modified nucleotide may have an unmodified sugar moiety and a modified phosphate group.
  • a modified nucleotide may have a modified sugar moiety and an unmodified nucleobase.
  • a modified nucleotide may have a modified sugar moiety and a modified phosphate group.
  • “Modified nucleobase” means a nucleobase having one or more alterations relative to a naturally occurring nucleobase.
  • “Modified phosphate group” means any change from a naturally occurring phosphate group of a nucleotide.
  • “Modified internucleotide linkage” means any change from a naturally occurring phosphodiester linkage between two nucleotides.
  • Phosphorothioate internucleotide linkage means a substituted phosphodiester internucleotide linkage where one of the non-bridging atoms is a sulfur atom.
  • Modified sugar moiety means a sugar of a nucleotide having any change and/or substitution from a naturally occurring sugar moiety.
  • “beta-D-deoxyribonucleoside” means a naturally occurring nucleoside monomer of DNA.
  • “beta-D-ribonucleoside” means a naturally occurring nucleoside monomer of RNA.
  • “2’-O-methyl sugar” or “2’-OMe sugar” means a sugar having an O-CH3 substitution at the 2’ position of the pentofuranosyl sugar.
  • “2’-O-methoxyethyl sugar” or “2’-MOE sugar” means a sugar having an OCH2CH2OCH3 substitution at the 2’ position of the pentofuranosyl sugar.
  • “2’-fluoro sugar” or “2’-F sugar” means a sugar having a fluoro substitution at the 2’ position of the pentofuranosyl sugar.
  • “Bicyclic sugar” means a modified sugar moiety comprising a linkage connecting the 2’-carbon and 4’-carbon of the pentafuranosyl sugar, resulting in a bicyclic structure.
  • Nonlimiting exemplary bicyclic sugar moieties include LNA, ENA, cEt, S-cEt, and R-cEt.
  • LNA sugar means a substituted sugar moiety comprising a - CH2-O- linkage between the 4’ and 2’ furanose ring atoms.
  • ENA sugar means a substituted sugar moiety comprising a -(CH2)2-O- linkage between the 4’ and 2’ furanose ring atoms.
  • 2’-O-methyl nucleotide means a nucleotide having an O-methyl substitution at the 2’ position of the pentofuranosyl sugar.
  • a 2’-O-methyl nucleotide may have a further modification in addition to the modified sugar moiety, for example a modified nucleobase and/or phosphate group.
  • “2’-fluoro nucleotide” means a nucleotide having a fluoro substitution at the 2’ position of the pentofuranosyl sugar.
  • a 2’-O-fluoro nucleotide may have a further modification in addition to the modified sugar moiety, for example a modified nucleobase and/or phosphate group.
  • “Bicyclic nucleotide” means a nucleotide having a linkage connecting the 2’-carbon and 4’-carbon of the pentafuranosyl sugar.
  • a bicyclic nucleotide may have a further modification in addition to the modified sugar moiety, for example a modified nucleobase and/or phosphate group.
  • “Pharmaceutical salt” means a salt form of a compound that retains the biological effectiveness and properties of a compound and does not have undesired effects when administered to a subject. “Therapeutically effective amount” means an amount sufficient for a compound to provide a therapeutic benefit to a subject. “Subject” used herein means a human or non-human animal selected for treatment or therapy. In embodiments, a subject is a human. “Administration” means providing a pharmaceutical agent or composition to a subject, and includes administration performed by a medical professional and self-administration. In embodiments, administration is intraocular administration. In embodiments, administration is topical administration.
  • Treating” or “treatment” means the administration of one or more pharmaceutical agents to a subject to achieve a desired clinical result, including but not limited to the alleviation, amelioration, or slowing of the progression of at least one indicator or symptom of a disease in a subject.
  • Prevent the onset of means the prevention of the appearance of at least one indicator or symptom of a disease in a subject at risk for developing the disease.
  • Effective amount means an amount sufficient for a compound that, when administered to a subject, is sufficient to effect treatment of a disease in the subject.
  • an effective amount may vary depending on the one or more of the compound, its mode of administration, the severity of the disease in the subject, concomitant pharmaceutical agents the subject is receiving, and characteristics of the subject such as the subject’s medical history, age, and weight.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals.
  • the alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons). In embodiments, the alkyl is fully saturated.
  • the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).
  • An alkyl moiety may be an alkenyl moiety.
  • An alkyl moiety may be an alkynyl moiety.
  • An alkyl moiety may be fully saturated.
  • An alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds.
  • An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds.
  • cycloalkyl means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system.
  • monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic.
  • cycloalkyl groups are fully saturated.
  • monocyclic cycloalkyls examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings.
  • bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH 2 ) w , where w is 1, 2, or 3).
  • alkylene bridge of between one and three additional carbon atoms
  • a bridging group of the form (CH 2 ) w i.e., a bridging group of the form (CH 2 ) w , where w is 1, 2, or 3).
  • bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.
  • fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl.
  • the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring.
  • cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia.
  • multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl.
  • multicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring.
  • multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.
  • multicyclic cycloalkyl groups include, but are not limited to tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl, and perhydrophenoxazin-1-yl.
  • a cycloalkyl is a cycloalkenyl.
  • the term “cycloalkenyl” is used in accordance with its plain ordinary meaning.
  • a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system.
  • monocyclic cycloalkenyl ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon carbon double bond), but not aromatic.
  • monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl.
  • bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings.
  • bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH2)w, where w is 1, 2, or 3).
  • alkylene bridge of between one and three additional carbon atoms
  • bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct 2 enyl.
  • fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl.
  • the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring.
  • cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl.
  • multicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring.
  • multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.
  • a heterocycloalkyl is a heterocyclyl.
  • heterocyclyl as used herein, means a monocyclic, bicyclic, or multicyclic heterocycle.
  • the heterocyclyl monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic.
  • the 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S.
  • the 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle.
  • heterocyclyl monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3 dioxanyl, 1,3 dioxolanyl, 1,3 dithiolanyl, 1,3 dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl
  • the heterocyclyl bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl.
  • the heterocyclyl bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system.
  • bicyclic heterocyclyls include, but are not limited to, 2,3 dihydrobenzofuran 2 yl, 2,3 dihydrobenzofuran 3 yl, indolin 1 yl, indolin 2 yl, indolin 3 yl, 2,3 dihydrobenzothien 2 yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro 1H indolyl, and octahydrobenzofuranyl.
  • heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia.
  • the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia.
  • Multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl.
  • multicyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring.
  • multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.
  • multicyclic heterocyclyl groups include, but are not limited to 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl, 9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl.
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH2CH2CH2CH2-.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • alkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
  • alkynylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne.
  • the alkylene is fully saturated.
  • the alkylene is monounsaturated.
  • the alkylene is polyunsaturated.
  • An alkenylene includes one or more double bondss.
  • An alkynylene includes one or more triple bonds.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, S, Si, or P), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) e.g., O, N, S, Si, or P
  • Heteroalkyl is an uncyclized chain.
  • a heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • the term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond.
  • a heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds.
  • heteroalkynyl by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond.
  • a heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds.
  • the heteroalkyl is fully saturated.
  • the heteroalkyl is monounsaturated.
  • the heteroalkyl is polyunsaturated.
  • the term “heteroalkylene,” by itself or as part of another substituent means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-.
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO 2 R'.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity.
  • heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like.
  • heteroalkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene.
  • heteroalkynylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne.
  • the heteroalkylene is fully saturated.
  • the heteroalkylene is monounsaturated.
  • the heteroalkylene is polyunsaturated.
  • a heteroalkenylene includes one or more double bonds.
  • a heteroalkynylene includes one or more triple bonds.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
  • the cycloalkyl is fully saturated.
  • the cycloalkyl is monounsaturated.
  • the cycloalkyl is polyunsaturated.
  • the heterocycloalkyl is fully saturated.
  • the heterocycloalkyl is monounsaturated.
  • the heterocycloalkyl is polyunsaturated.
  • halo or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(C1-C4)alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • acyl means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within an aryl ring of the multiple rings.
  • heteroaryl refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring).
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heteroaromatic ring of the multiple rings).
  • a 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazo
  • Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
  • a heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.
  • Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings.
  • Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g.
  • heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring.
  • substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.
  • the symbol “ ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.
  • alkylarylene as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker).
  • alkylarylene group has the formula: .
  • An alkylarylene moiety may be substituted (e.g. with a substituent group) on the alkylene moiety or the arylene linker (e.g.
  • alkylarylene is unsubstituted.
  • alkyl e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl”
  • alkyl e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl”
  • Preferred substituents for each type of radical are provided below.
  • R, R', R'', R'', and R''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • aryl e.g., aryl substituted with 1-3 halogens
  • substituted or unsubstituted heteroaryl substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R', R'', R''', and R''' group when more than one of these groups is present.
  • R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring.
  • -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).
  • haloalkyl e.g., -CF 3 and -CH 2 CF 3
  • acyl e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like.
  • each of the R groups is independently selected as are each R', R'', R'', and R''' groups when more than one of these groups is present.
  • Substituents for rings e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene
  • substituents on the ring may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent).
  • the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings).
  • the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different.
  • a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent)
  • the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency.
  • a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms.
  • the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.
  • Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.
  • Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure.
  • the ring-forming substituents are attached to adjacent members of the base structure.
  • two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member of the base structure.
  • two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring-forming substituents are attached to non-adjacent members of the base structure.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-, wherein T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O) -, -S(O) 2 -, -S(O) 2 NR'-, or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X'- (C''R''R'') d -, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-.
  • R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • heteroatom or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
  • a “substituent group,” as used herein, means a group selected from the following moieties: (A) oxo, halogen, –CF 3 , –CCl 3 , –CBr 3 , –CI 3 , –CHF 2 , –CHCl 2 , –CHBr 2 , –CHI 2 , -CH2F, –CH2Cl, –CH2Br, –CH2I, -CN, -N3, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SCH3, -SO3H, -SO4H, -SO2NH2, ⁇ NH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, –OCF3, –OCCl3, –OCBr3, –OC
  • a “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a
  • a “lower substituent” or “ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or un
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alky
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one substituent group wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one size-limited substituent group wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different.
  • each size-limited substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • each lower substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • each substituted or unsubstituted alkyl may be a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C1-C20 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 2 to 20 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
  • each substituted or unsubstituted alkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C1-C20 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 2 to 20 membered heteroalkylene
  • each substituted or unsubstituted cycloalkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C 3 -C 8 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower
  • each substituted or unsubstituted alkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C 1 -C 8 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C3-C7 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent
  • each substituted or unsubstituted alkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C1-C8 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 2 to 8 membered heteroalkylene
  • each substituted or unsubstituted cycloalkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C3-C7 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstitute
  • the compound is a chemical species set forth in the Examples section, figures, or tables below.
  • Certain compounds provided herein possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure.
  • the compounds of provided herein do not include those that are known in art to be too unstable to synthesize and/or isolate.
  • Compounds provided herein include those in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the (R) and (S) configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds, generally recognized as stable by those skilled in the art, are within the scope of the present disclosure. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, replacement of fluoride by 18 F, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds provided herein, whether radioactive or not, are inlcuded within the present disclosure.
  • each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.
  • an analog is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.
  • the terms "a” or "an,” as used in herein means one or more.
  • substituted with a[n] means the specified group may be substituted with one or more of any or all of the named substituents.
  • a group such as an alkyl or heteroaryl group, is "substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl,” the group may contain one or more unsubstituted C 1 -C 20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • R substituent
  • the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different.
  • R group is present in the description of a chemical genus (such as Formula (I))
  • a Roman decimal symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R 13 substituents are present, each R 13 substituent may be distinguished as R 13.1 , R 13.2 , R 13.3 , R 13.4 , etc., wherein each of R 13.1 , R 13.2 , R 13.3 , R 13.4 , etc.
  • R 13 is defined within the scope of the definition of R 13 and optionally differently.
  • the terms “a” or “an,” as used in herein means one or more.
  • the phrase “substituted with a[n],” as used herein, means the specified group may be substituted with one or more of any or all of the named substituents.
  • a group such as an alkyl or heteroaryl group, is "substituted with an unsubstituted C 1 -C 20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl," the group may contain one or more unsubstituted C 1 -C 20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • a compound is a double-stranded nucleic acid comprising an antisense strand complementary to the NRL mRNA and a sense strand complementary to the antisense strand.
  • the antisense strand and sense strand of a compound are two separate strands and are not covalently linked and form a small interfering RNA (siRNA).
  • the antisense strand and sense strand of a compound are covalently linked by a nucleotide linker to form a short hairpin RNA (shRNA).
  • the compound is a single-stranded nucleic acid comprising an antisense strand complementary to the NRL mRNA (ssRNAi).
  • NRL neural retina leucine zipper
  • the compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, each of the antisense strand and sense strands is 15 to 25 nucleotides in length, the antisense strand comprises a nucleotide sequence that is at least 90% complementary to at least 15 contiguous nucleotides of any one of nucleotides 501 to 563 of SEQ ID NO: 1, nucleotides 602 to 626 of SEQ ID NO: 1, nucleotides 623 to 654 of SEQ ID NO: 1, nucleotides 741 to 765 of SEQ ID NO: 1, nucleotides 759 to 777 of SEQ ID NO: 1, nucleotides 882 to 909 of SEQ ID NO: 1, or nucleotides 1111 to 1133 of SEQ ID NO: 1, and the nucleotide sequence of the sense strand
  • NRL neural retina leucine zipper
  • NRL neural retina leucine zipper
  • the compound is a single-stranded nucleic acid comprising an antisense strand
  • the antisense strand is 15 to 25 nucleotides in length and the antisense strand comprises a nucleotide sequence that is at least 90% complementary to at least 15 contiguous nucleotides of any one of nucleotides 501 to 563 of SEQ ID NO: 1, nucleotides 602 to 626 of SEQ ID NO: 1, nucleotides 623 to 654 of SEQ ID NO: 1, nucleotides 741 to 765 of SEQ ID NO: 1, nucleotides 759 to 777 of SEQ ID NO: 1, nucleotides 882 to 909 of SEQ ID NO: 1, or nucleotides 1111 to 1133 of SEQ ID NO: 1.
  • nucleotide sequences of sense and antisense strands are shown in Table 1. “Start” and “End” correspond to the 5’ and 3’ nucleotide positions of the nucleotide sequence of the human NRL mRNA) to which the nucleotides of the sense strand, excluding any thymine bases, are identical, and the 5’ and 3’ nucleotide positions of the nucleotide sequence of the human NRL mRNA (SEQ ID NO: 1) to which the nucleotides the antisense strand, excluding any thymine bases, are complementary.
  • a double-stranded compound provided herein may comprise any pair of sense strand and antisense strand described in Table 1.
  • a single-stranded nucleic acid may comprise any antisense strand described in Table 1. Table 1: Unmodified Nucleotide Sequences
  • an antisense strand may apply to the antisense strand of a single-stranded nucleic acid or a double-stranded nucleic acid.
  • an embodiment of a sense strand may apply to a sense strand of any double-stranded nucleic acid provided herein, including siRNAs and shRNAs.
  • an antisense strand is 15 to 25 nucleotides in length.
  • an antisense strand is 17 to 23 nucleotides in length.
  • an antisense strand is 19 to 21 nucleotides in length.
  • an antisense strand is 21 to 23 nucleotides in length. In embodiments, an antisense strand is 15 nucleotides in length. In embodiments, an antisense strand is 16 nucleotides in length. In embodiments, an antisense strand is 17 nucleotides in length. In embodiments, an antisense strand is 18 nucleotides in length. In embodiments, an antisense strand is 19 nucleotides in length. In embodiments, an antisense strand is 20 nucleotides in length. In embodiments, an antisense strand is 21 nucleotides in length. In embodiments, an antisense strand is 22 nucleotides in length.
  • an antisense strand is 23 nucleotides in length. In embodiments, an antisense strand is 24 nucleotides in length. In embodiments, an antisense strand is 25 nucleotides in length. In embodiments, a sense strand is 15 to 25 nucleotides in length. In embodiments, a sense strand is 17 to 23 nucleotides in length. In embodiments, a sense strand is 19 to 21 nucleotides in length. In embodiments, a sense strand is 21 to 23 nucleotides in length. In embodiments, a sense strand is 15 nucleotides in length. In embodiments, a sense strand is 16 nucleotides in length.
  • a sense strand is 17 nucleotides in length. In embodiments, a sense strand is 18 nucleotides in length. In embodiments, a sense strand is 19 nucleotides in length. In embodiments, a sense strand is 20 nucleotides in length. In embodiments, a sense strand is 21 nucleotides in length. In embodiments, a sense strand is 22 nucleotides in length. In embodiments, a sense strand is 23 nucleotides in length. In embodiments, a sense strand is 24 nucleotides in length. In embodiments, a sense strand is 25 nucleotides in length.
  • the length of the sense strand is identical to the length of the antisense strand. In embodiments, the length of the sense strand is greater than the length of the antisense strand. In embodiments, the length of the sense strand is less than the length of the antisense strand.
  • the double-stranded region of a double-stranded nucleic acid may be from 15 to 25 nucleobase pairs in length, depending on the lengths of the sense strand and the antisense strand. In embodiments, the double-stranded region is 17 to 23 nucleobase pairs in length. In embodiments, the double-stranded region is 19 to 21 nucleobase pairs in length. In embodiments, the double-stranded region is 21 to 23 nucleotides in length.
  • the double-stranded region is 15 nucleobase pairs in length. In embodiments, the double-stranded region is 16 nucleobase pairs in length. In embodiments, the double-stranded region is 17 nucleobase pairs in length. In embodiments, the double-stranded region is 18 nucleobase pairs in length. In embodiments, the double-stranded region is 19 nucleobase pairs in length. In embodiments, the double-stranded region is 20 nucleobase pairs in length. In embodiments, the double-stranded region is 21 nucleobase pairs in length. In embodiments, the double-stranded region is 22 nucleobase pairs in length. In embodiments, the double-stranded region is 23 nucleobase pairs in length.
  • the double-stranded region is 24 nucleobase pairs in length. In embodiments, the double-stranded region is 25 nucleobase pairs in length. In embodiments, the nucleotide sequence of a sense strand has no more than one mismatch to the nucleotide sequence of an antisense strand of a double-stranded nucleic acid. In embodiments, the nucleotide sequence of a sense strand has no mismatches to the nucleotide sequence of an antisense strand of a double-stranded nucleic acid.
  • Single-stranded nucleotide overhangs and nucleotide linkers are not considered for the purposes of determining the number of mismatches within the double-stranded region of a double-stranded nucleic acid provided herein.
  • a double-stranded nucleic acid comprising an antisense strand that is 23 nucleotides in length, and a sense strand that is 21 nucleotides in length have no mismatches over the double-stranded region, provided the nucleotide sequence of the sense strand is fully complementary over its length the nucleotide sequence of the antisense strand.
  • a double-stranded nucleic acid comprising a sense strand that is 20 nucleotides in length, an antisense strand that is 22 nucleotides in length, and a nucleotide linker that is eight nucleotides in length, may have no mismatches over the double-stranded region provided the nucleotide sequence of the sense strand is fully complementary over its length to the nucleotide sequence of the antisense strand.
  • a double-stranded nucleic acid comprises an antisense strand of 19 nucleotides in length and a sense strand of 19 nucleotides in length.
  • the antisense strand is 22 nucleotides in length and the sense strand is 20 nucleotides in length. In embodiments, the antisense strand is 23 nucleotides in length and the sense strand is 21 nucleotides in length. In embodiments, the antisense strand is 23 nucleotides in length including two deoxythymidines at the 3’ terminus, and the sense strand is 21 nucleotides in length including two deoxythymidines at the 3’ terminus.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 16 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 17 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 18 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 19 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 20 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 21 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 23 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 24 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to 25 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 95% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand comprises at least 15 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75.
  • the nucleotide sequence of antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20, or 21 nucleotides of a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75.
  • the nucleotide sequence of antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75.
  • the nucleotide sequence of the antisense strand comprises at least 15 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 213, 215, 217, 224, 241, 226, 228, and 230.
  • the nucleotide sequence of antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20, or 21 nucleotides of a nucleotide sequence selected from SEQ ID NO: 213, 215, 217, 224, 241, 226, 228, and 230. In embodiments, the nucleotide sequence of antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 213, 215, 217, 224, 241, 226, 228, and 230.
  • the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75.
  • the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75, and wherein the nucleotide sequence of the antisense strand is 100% complementary to 23 contiguous nucleotides of SEQ ID NO: 1.
  • the nucleotide sequence of the sense strand comprises 19 contiguous of a nucleotide sequence selected from SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74.
  • the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74.
  • the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74.
  • the sense strand is 21 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1.
  • the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236.
  • the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236, and wherein the nucleotide sequence of the antisense strand is 100% complementary to 23 contiguous nucleotides of SEQ ID NO: 1.
  • the nucleotide sequence of the sense strand comprises 19 contiguous of a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236.
  • the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236.
  • the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236.
  • the sense strand is 21 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 16 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 17 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 18 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 19 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 20 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 21 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 23 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 24 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to 25 contiguous nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 95% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand comprises at least 15 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 93, 95, and 97.
  • nucleotide sequence of antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20, or 21 nucleotides of a nucleotide sequence selected from SEQ ID NO: 93, 95, and 97.
  • the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 93, 95, and 97.
  • the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 93, 95, and 97.
  • the antisense strand is 23 nucleotides in length and comprises a nucleotide sequence identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96, and wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1.
  • the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96.
  • the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96. In embodiments, the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96.
  • the sense strand is 21 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 16 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 17 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 18 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 19 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 20 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 21 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 23 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 24 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to 25 contiguous nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 95% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to the recited region of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand comprises at least 15 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109. In embodiments, nucleotide sequence of antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20, or 21 nucleotides of a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109. In embodiments, the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109.
  • the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109.
  • the antisense strand is 23 nucleotides in length and comprises a nucleotide sequence identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109, and wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1.
  • the nucleotide sequence of the sense strand comprises 19 contiguous of a nucleotide sequence selected from SEQ ID NO: 8, 10, 2, 4, 104, 106, and 108.
  • the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 8, 10, 2, 4, 104, 106, and 108.
  • the sense strand is 19 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 8, 10, 2, 4, 104, 106, and 108.
  • the sense strand is 21 nucleotides in length and comprises a nucleotide sequence comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 8, 10, 2, 4, 104, 106, and 108, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1.
  • the nucleotide sequence of the sense strand comprises 19 contiguous of a nucleotide sequence selected from SEQ ID NO: 268 and 269.
  • the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 268 and 269.
  • the sense strand is 19 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 268 and 269.
  • the sense strand is 21 nucleotides in length and comprises a nucleotide sequence comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 268 and 269, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 16 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 17 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 18 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 19 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 20 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 21 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 23 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 24 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to 25 contiguous nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 95% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand comprises at least 15 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119. In embodiments, nucleotide sequence of antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20, or 21 nucleotides of a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119.
  • the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119.
  • the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119.
  • the antisense strand is 23 nucleotides in length and comprises a nucleotide sequence identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119, wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1.
  • the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 114, 116, and 118.
  • the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 114, 116, and 118. In embodiments, the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 114, 116, and 118.
  • the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 114, 116, and 118, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 16 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 17 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 18 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 19 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 20 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 21 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 23 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 24 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to 25 contiguous nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 95% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand comprises at least 15 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133.
  • nucleotide sequence of antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20, or 21 nucleotides of the antisense strand of a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133.
  • the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133.
  • the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133.
  • the antisense strand is 23 nucleotides in length and comprises a nucleotide sequence identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133, and wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1.
  • the nucleotide sequence of the sense strand comprises 19 linked nucleotides of a nucleotide sequence selected from SEQ ID NO: 128, 130, and 132.
  • the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 128, 130, and 132. In embodiments, the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 128, 130, and 132.
  • the sense strand is 21 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 128, 130, and 132, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1.
  • the nucleotide sequence of the sense strand comprises 19 linked nucleotides of the nucleotide sequence of SEQ ID NO: 237.
  • the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to the nucleotide sequence of SEQ ID NO: 237.
  • the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of the nucleotide sequence of SEQ ID NO: 237.
  • the sense strand is 21 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of the nucleotide sequence of SEQ ID NO: 237, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 16 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 17 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 18 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 19 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 20 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 21 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 23 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 24 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to 25 contiguous nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 95% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand comprises at least 15 contiguous nucleotides of nucleotides of SEQ ID NO: 141. In embodiments, the nucleotide sequence of antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20, or 21 nucleotides of SEQ ID NO: 141.
  • the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence of SEQ ID NO: 141.
  • the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to the nucleotide sequence of SEQ ID NO: 141.
  • the antisense strand is 23 nucleotides in length and comprises a nucleotide sequence identical to nucleotides 1 to 19 of the nucleotide sequence of SEQ ID NO: 141, and wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1.
  • the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 140. In embodiments, the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to the nucleotide sequence of SEQ ID NO: 140. In embodiments, the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to the nucleotide sequence of SEQ ID NO: 140.
  • the sense strand is 21 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of the nucleotide sequence of SEQ ID NO: 140, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 16 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 17 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 18 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 19 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 20 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 21 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 23 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 24 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to 25 contiguous nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 95% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to the recited region of SEQ ID NO: 1.
  • the antisense strand comprises at least 15 contiguous nucleotides of the antisense strand of a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19. In embodiments, the antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20 or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19. In embodiments, the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19.
  • the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to the nucleotide sequence of a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19.
  • the antisense strand is 23 nucleotides in length and comprises a nucleotide sequence identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19, and wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1.
  • the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 170, 172, 22, 12, 14, 16, and 18.
  • the nucleotide sequence of the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical a nucleotide sequence selected from SEQ ID NO: 170, 172, 22, 12, 14, 16, and 18.
  • the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID: 170, 172, 22, 12, 14, 16, and 18.
  • the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID: 170, 172, 22, 12, 14, 16, and 18, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1.
  • the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 238, 273, 270, 271, and 272.
  • the nucleotide sequence of the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical a nucleotide sequence selected from SEQ ID NO: 238, 273, 270, 271, and 272.
  • the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID: 238, 273, 270, 271, and 272.
  • the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID: 238, 273, 270, 271, and 272, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 16 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 17 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 18 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 19 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 20 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 21 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 23 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1.
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 24 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to 25 contiguous nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 95% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to the recited region of SEQ ID NO: 1.
  • the antisense strand comprises at least 15 contiguous nucleotides of the antisense strand of a nucleotide sequence selected from SEQ ID NO: 193 and 195. In embodiments, the antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20 or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 193 and 195. In embodiments, the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 193 and 195.
  • the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 193 and 195.
  • the antisense strand is 23 nucleotides in length and comprises a nucleotide sequence identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 193 and 195, and wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1.
  • the nucleotide sequence of the sense strand comprises 19 contiguous of a nucleotide sequence selected from SEQ ID NO: 193 and 195.
  • the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 192 and 194. In embodiments, the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from from SEQ ID NO: 192 and 194.
  • the sense strand is 21 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 192 and 194, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1.
  • the terminal nucleotides may form a nucleobase pair, in which case the end of the double-stranded nucleic acid is a blunt end.
  • one or more unpaired nucleotides of an antisense strand and/or sense strand may extend beyond the terminus of the complementary strand, resulting in a nucleotide overhang of one or more terminal single-stranded nucleotides.
  • at least one of the 5’ and 3’ terminus of a double-stranded nucleic acid is a blunt end.
  • both the 5’ terminus and 3’ terminus of the double-stranded nucleic acid are blunt ends.
  • at least one end of the double-stranded nucleic acid comprises a nucleotide overhang.
  • each end of the double-stranded nucleic acid comprises a nucleotide overhang.
  • one end of the double-stranded nucleic acid is a blunt end and the other end of the double-stranded nucleic acid comprises a nucleotide overhang.
  • the antisense strand comprises a nucleotide overhang at its 3’ terminus.
  • the sense strand comprises a nucleotide overhang at its 3’ terminus.
  • each of the antisense strand and sense strand comprises a nucleotide overhang at its 3’ terminus.
  • at least one of the antisense strand and sense strand comprises a nucleotide overhang at its 5’ terminus.
  • each of the antisense strand and sense strand comprises a nucleotide overhang at each 5’ terminus.
  • a nucleotide overhang is from one to five single-stranded nucleotides.
  • a nucleotide overhang is one single-stranded nucleotide.
  • a nucleotide overhang is two single-stranded nucleotides.
  • a nucleotide overhang is three single-stranded nucleotides.
  • a nucleotide overhang is three single-stranded nucleotides.
  • a nucleotide overhang is four single-stranded nucleotides.
  • a nucleotide overhang is five single-stranded nucleotides. In embodiments, at least one of the single-stranded nucleotides of a nucleotide overhang is a modified nucleotide. In embodiments, each of the single-stranded nucleotides of a nucleotide overhang is a modified nucleotide. In embodiments, the modified nucleotide is a 2’-O-methyl nucleotide. In embodiments, the nucleotide overhang is two single-stranded nucleotides, and each nucleotide is a 2’-O-methoxyethyl nucleotide.
  • At least one nucleotide of the nucleotide overhang at the 3’ terminus of an antisense strand is complementary to a corresponding nucleotide of SEQ ID NO: 1. In embodiments, each nucleotide of the nucleotide overhang at the 3’ terminus of an antisense strand is complementary to a corresponding nucleotide of SEQ ID NO: 1. In some embodiment, at least one nucleotide of the nucleotide overhang at the 3’ terminus of an antisense strand is not complementary to a corresponding nucleotide of SEQ ID NO: 1.
  • each nucleotide of the nucleotide overhang at the 3’ terminus of an antisense strand is not complementary to a corresponding nucleotide of SEQ ID NO: 1.
  • at least one single-stranded nucleotide of a nucleotide overhang is a deoxythymidine nucleotide.
  • a nucleotide overhang is two single-stranded nucleotides, and each nucleotide is a deoxythymidine nucleotide.
  • the nucleotide sequence of the antisense strand comprises a nucleotide overhang of two deoxythymidine nucleotides.
  • the sense strand comprises a nucleotide overhang of two deoxythymidine nucleotides.
  • the antisense strand and the sense strand comprise a nucleotide overhang of two deoxythymidine nucleotides.
  • Non-limiting examples of double-stranded nucleic acids comprising blunt ends or nucleotide overhangs are provided in Table 2 below.
  • the antisense strand is 21 nucleotides in length and the sense strand is 21 nucleotides in length, and the nucleotide sequence of the antisense strand is fully complementary to the nucleotide sequence of the sense strand over the double-stranded region, the length of the double-stranded region is 19 nucleobase pairs and each terminus of the double-stranded nucleic acid has a dTdT overhang.
  • the antisense strand is 21 nucleotides in length and the sense strand is 19 nucleotides in length
  • the nucleotide sequence of the antisense strand is fully complementary to the nucleotide sequence of the sense strand over the double-stranded region
  • the length of the double-stranded region is 19 nucleobase pairs and the 3’ terminus of the antisense strand comprises a dTdT overhang.
  • the antisense strand is 19 nucleotides in length and the sense strand is 19 nucleotides in length, and the nucleotide sequence of the antisense strand is fully complementary to the nucleotide sequence of the sense strand over the double-stranded region, the length of the double-stranded region is 19 nucleobase pairs, and each terminus is a blunt end.
  • the antisense strand is 23 nucleotides in length and the sense strand is 21 nucleotides in length
  • the length of the double-stranded region is 21 nucleobase pairs and 3’ terminus of the antisense strand comprises a two-nucleotide overhang.
  • the termini that are not connected by the nucleotide linker may form a blunt end or may form a nucleotide overhang of one or more single-stranded nucleotides.
  • the non-linked end of the double-stranded nucleic acid is a blunt end.
  • the non-linked end comprises a nucleotide overhang of one or more single-stranded nucleotides.
  • the non-linked end of the guide strand comprises a nucleotide overhang.
  • the non-linked end of the sense strand comprises a nucleotide overhang.
  • the 3’ terminus of the guide strand comprises a nucleotide overhang.
  • the 3’ terminus of the sense strand comprises a nucleotide overhang.
  • the 5’ terminus of the sense strand comprises a nucleotide overhang.
  • the 5’ terminus of the sense strand comprises a nucleotide overhang.
  • the nucleotide linker is four to 16 nucleotides in length.
  • the nucleotide linker is four nucleotides in length. In embodiments, the nucleotide linker is four nucleotides in length. In embodiments, the nucleotide linker is five nucleotides in length. In embodiments, the nucleotide linker is six nucleotides in length. In embodiments, the nucleotide linker is seven nucleotides in length. In embodiments, the nucleotide linker is eight nucleotides in length. In embodiments, the nucleotide linker is nine nucleotides in length. In embodiments, the nucleotide linker is 10 nucleotides in length.
  • the nucleotide linker is 11 nucleotides in length. In embodiments, the nucleotide linker is 12 nucleotides in length. In embodiments, the nucleotide linker is 13 nucleotides in length. In embodiments, the nucleotide linker is 14 nucleotides in length. In embodiments, the nucleotide linker is 15 nucleotides in length. In embodiments, the nucleotide linker is 16 nucleotides in length.
  • RNA Ribonucleic acid
  • DNA DNA
  • nucleic acid having the nucleotide sequence "ATCGATCG” in the sequence listing encompasses any nucleic acid having such nucleotide sequence, whether modified or unmodified, including, but not limited to, such nucleic acids comprising RNA bases, such as those having sequence "AUCGAUCG” and those having some DNA bases and some RNA bases such as “AUCGATCG” and oligonucleotides having other modified bases, such as "ATmeCGAUCG,” wherein meC indicates a 5-methylcytosine.
  • Modified Nucleotides Double-stranded and single-stranded nucleic acids provided herein may comprise one or more modified nucleotides.
  • a modified nucleotide may be selected over an unmodified form because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for other oligonucleotides or nucleic acid targets, increased stability in the presence of nucleases, and/or reduced immune stimulation.
  • at least one nucleotide of the antisense strand is a modified nucleotide.
  • at least one nucleotide of the sense strand is a modified nucleotide.
  • each nucleotide of the antisense strand forming the double-stranded region is a modified nucleotide.
  • each nucleotide of the sense strand forming the double-stranded region comprises is a modified nucleotide.
  • a modified nucleotide comprises one or more of a modified sugar moiety, a modified internucleotide linkage, and a 5’-terminal modified phosphate group.
  • a modified nucleotide comprises a modified sugar moiety.
  • a modified nucleotide comprises a modified internucleotide linkage.
  • a modified nucleotide comprises a modified nucleobase.
  • a modified nucleotide comprises a modified 5’-terminal phosphate group.
  • a modified nucleotide comprises a modification at the 5’ carbon of the pentafuranosyl sugar. In embodiments, a modified nucleotide comprises a modification at the 3’ carbon of the pentafuranosyl sugar. In embodiments, a modified nucleotide comprises a modification at the 2’ carbon of the pentafuranosyl sugar. In embodiments, a modified nucleotide is at the 5’ terminus of an antisense strand or sense strand. In embodiments, a modified nucleotide is at the 3’ terminus of an antisense strand or sense strand.
  • a modified nucleotide is at an internal nucleotide of an antisense strand or sense strand.
  • a modified nucleotide comprises a ligand attached to the 2’, 3, or 5’ carbon of the pentafuranosyl sugar.
  • a nucleotide comprises a ligand attached to a nucleobase.
  • a modified nucleotide may comprise a modified sugar moiety, a naturally occurring nucleobase, and a naturally occurring internucleotide linkage.
  • a modified nucleotide may comprise a modified sugar moiety, a naturally occurring nucleobase, and a modified internucleotide linkage.
  • a modified sugar moiety is modified at the 2’ carbon of the pentafuranosyl sugar, relative to the naturally occurring 2’-OH of RNA or the 2’-H of DNA.
  • a modified sugar moiety is a 2’-fluoro sugar (also referred to as a 2’-F sugar).
  • a modified sugar moiety is a 2’-O-methyl sugar (also referred to as a "2 '-OMe sugar” or a “2’-OCH 3 ” sugar).
  • a modified sugar moiety is a 2’-O-methoxyethyl sugar (also referred to as a 2’-OCH2CH2OCH3 or a 2’-MOE sugar).
  • the modified nucleotide comprising a modified sugar moiety is selected from a 2’-fluoro nucleotide, a 2’-O-methyl nucleotide, a 2’-O-methoxyethyl nucleotide, and a bicyclic sugar nucleotide.
  • a modified nucleotide is a 2’-fluoro nucleotide, where the 2’ carbon of the pentafuranosyl sugar has a fluoro substitution.
  • a modified nucleotide is a 2’-O-methyl nucleotide, where the 2’ carbon of the pentafuranosyl sugar has a 2’-O methyl substitution.
  • a modified nucleotide is a 2’-O-methoxyethyl nucleotide, where the 2’ carbon of the pentafuranosyl sugar has a 2’-O-methoxyethyl substitution.
  • Other modified nucleotides may be similarly named.
  • a modified nucleotide comprises a modified sugar moiety, where the ribose has a covalent linkage between the 2’ and 4’ carbons.
  • Such a modified sugar moiety may be referred to as a “bicyclic sugar,” and nucleotides comprising such sugar moieties may be referred to as “bicyclic nucleic acids.”
  • the covalent linkage of a bicyclic sugar is a methyleneoxy linkage (4'-CH2-O-2'), also known as “LNA.”
  • the covalent linkage of a bicyclic sugar is an ethyleneoxy linkage (4'-(CH2)2-O-2'), also known as “ENA.”
  • the covalent linkage of a bicyclic moiety is a methyl(methyleneoxy) linkage (4'-CH(CH3)-O-2'), also known as “constrained ethyl” or “cEt.”
  • the -CH(CH3)- bridge is constrained in the S orientation (“S-cEt”).
  • the -CH(CH 3 )- bridge is constrained in the R orientation (“R-cEt”).
  • the covalent linkage of a bicyclic sugar is a (4'-CH(CH2-OMe)-O-2' linkage, also known as “c-MOE.”
  • the bicyclic sugar is a D sugar in the alpha configuration.
  • the bicyclic sugar is a D sugar in the beta configuration.
  • the bicyclic sugar is an L sugar in the alpha configuration.
  • the bicyclic sugar is an L sugar in the beta configuration.
  • a modified sugar moiety is a 1,5-anhydrohexitol nucleic acid, also known as a “hexitol nucleic acid” or “HNA.”
  • the oxygen of the pentafuranosyl sugar is replace with a sulfur, to form a thio-sugar.
  • a thio-sugar is modified at the 2’ carbon.
  • a modified internucleotide linkage is a phosphorothioate internucleotide linkage.
  • a modified internucleotide linkage is a methylphosphonate internucleotide linkage.
  • the first two internucleotide linkages at the 5’ terminus of the sense strand and the last two internucleotide linkages at the 3’ terminus of the sense strand are phosphorothioate internucleotide linkages.
  • the first two internucleotide linkages at the 5’ terminus of the antisense strand and the last two internucleotide linkages at the 3’ terminus of the antisense strand are phosphorothioate internucleotide linkages.
  • the first two internucleotide linkages at the 5’ terminus of the sense strand and the last two internucleotide linkages at the 3’ terminus of the sense strand are phosphorothioate internucleotide linkages
  • the first two internucleotide linkages at the 5’ terminus of the antisense strand and the last two internucleotide linkages at the 3’ terminus of the antisense strand are phosphorothioate internucleotide linkages.
  • a modified nucleobase is selected from 5-hydroxymethyl cytosine, 7-deazaguanine and 7-deazaadenine.
  • a modified nucleobase is selected from 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone.
  • a modified nucleobase is selected from 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2 aminopropyladenine, 5-propynyluracil and 5-propynylcytosine.
  • a modified nucleotide comprises a modification of the phosphate group at the 4’-carbon of the pentafuranosyl sugar.
  • the modified phosphate group is 5’-(E)-vinylphosphonate.
  • a modified nucleotide is a phosphorodiamidite-linked morpholino nucleotide.
  • a modified nucleotide comprises an acyclic nucleoside derivative lacking the bond between the 2’ carbon and 3’ carbon of the sugar ring, also known as an “unlocked nucleic acid” or “UNA.”
  • the antisense strand is 21 nucleotides in length and the nucleotides of the antisense strand are modified such that, counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides, and nucleotides 20 and 21 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the
  • Such a modification pattern may be represented by the following Formula I: 5’-NM S NF S NMNFNMNFNMNFNMNFNMNFNMNFNMNFNMNFNMNFNMNFNMNFNM S N-3', wherein “NM” is a 2’-O-methyl nucleotide, “N F ” is a 2’-fluoro nucleotide, “N” is a beta-D-deoxynucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • the sense strand is 21 nucleotides in length and the nucleotides of the sense strand are modified such that, counting from the from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides, and nucleotides 20 and 21 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Such a modification pattern may be represented by the following Formula II: 5’-NF S NM S NFNMNFNMNFNMNFNMNFNMNFNMNFNMNFNMNFNMNFNMNFS N S N-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, “N” is a beta-D-deoxynucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • the antisense strand is 19 nucleotides in length and the nucleotides of the antisense strand are modified such that, counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Such a modification pattern may be represented by the following Formula III: 5’-N M S N F S N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F S N M -3', wherein “N M ” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, “N” is a beta-D-deoxynucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkages is a phosphodiester internucleotide linkage.
  • the sense strand is 19 nucleotides in length and the nucleotides of the sense strand are modified such that, counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoro nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide is a phosphodiester internucleotide linkage.
  • Such a modification pattern may be represented by the following Formula IV: 5’-NF S NM S NFNMNFNMNFNMNFNMNFNMNFNMNFNMNF S NM S NF-3', wherein “NM” is a 2’-O-methyl nucleotide, “N F ” is a 2’-fluoro nucleotide, “N” is a beta-D-deoxynucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphorodiester internucleotide linkage.
  • the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-fluoro nucleotides the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Such a modification pattern may be represented by the following Formula V: 5’-N M S N F S N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M S N M -3', wherein “N M ” is a 2’-O-methyl nucleotide, “N F ” is a 2’-fluoro nucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Such a modification pattern may be represented by the Formula VI: 5’-N F S N M S N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F S N M S N F -3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Such a modification pattern may be represented by the Formula VII: 5’-NM S NF S NMNFNMNFNMNFNMNFNMNMNMNMNFNMNFNMNFNMNFNM S NM S NM-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Such a modification pattern may be represented by the Formula VIII: 5’-NF S NM S NFNMNFNMNFNMNFNFNFNFNMNFNMNFNMNFNMNFS NM S NF-3', wherein “N M ” is a 2’-O-methyl nucleotide, “N F ” is a 2’-fluoro nucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Such a modification pattern may be represented by the Formula IX: 5’-N M S N F S N M N F N M N F N M N F N M N M N M N F N M N F N M N F N M N F N M N F N M S N M -3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Such a modification pattern may be represented by the Formula X: 5’-NF S NM S NFNMNFNMNFNMNFNFNFNFNMNFNMNFNMNFS NM S NF-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides
  • nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides
  • nucleotides 22 and 23 are beta-D-deoxynucleotides
  • the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages
  • each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Such a modification pattern may be represented by the Formula XI: 5’-N F S N M S N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F S N S N-3', wherein “N M ” is a 2’-O-methyl nucleotide, “N F ” is a 2’-fluoro nucleotide, “N” is a beta-D-deoxynucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Such a modification pattern may be represented by the Formula XII: 5’-NF S NM S NFNMNFNMNFNFNFNFNFNMNFNMNFNMNFNMNFNMNFNMNFS N S N-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, “N” is a beta-D-deoxynucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Such a modification pattern may be represented by the Formula XIII: 5’-N F S N M S N F N M N F N M N F N M N F N M N F N M N F N F N M N F N M N F S N S N-3', wherein “N M ” is a 2’-O-methyl nucleotide, “N F ” is a 2’-fluoro nucleotide, “N” is a beta-D-deoxynucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Such a modification pattern may be represented by the Formula XIV: 5’-N M S N M S N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F S N M S N F -3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded region, wherein the antisense strand and sense strand are not covalently linked (i.e. the antisense strand and sense strand form an siRNA), wherein the antisense strand is 21 nucleotides in length and the nucleotides of the antisense strand are modified such that, counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides, and nucleotides 20 and 21 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and
  • the antisense strand has the modification pattern represented by Formula I and the sense strand has the modification pattern represented by Formula II.
  • a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e.
  • the antisense strand and sense strand form an siRNA
  • the antisense strand is 19 nucleotides in length and the nucleotides of the antisense strand are modified such that, counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 21 nucleotide in length and the nucleotides of the sense strand are modified such that, counting from the 5’ terminus of the sense strand, nucleotides 1, 3,
  • the antisense strand has the modification pattern represented by Formula III and the sense strand has the modification pattern represented by Formula II.
  • a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e.
  • the antisense strand and sense strand form an siRNA
  • the antisense strand is 21 nucleotides in length and the nucleotides of the antisense strand are modified such that, counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides, and nucleotides 20 and 21 are beta-D-deoxy nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 19 nucleotide in length and the nucleotides of the sense strand are modified such
  • the antisense strand has the modification pattern represented by Formula I and the sense strand has the modification pattern represented by Formula IV.
  • a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e.
  • the antisense strand and sense strand form an siRNA
  • the antisense strand is 19 nucleotides in length and the nucleotides of the antisense strand are modified such that, counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide is a phosphodiester internucleotide linkage; and wherein the sense strand is 19 nucleotides in length and the nucleotides of the sense strand are modified such that, counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7,
  • the antisense strand has the modification pattern represented by Formula III and the sense strand has the modification pattern represented by Formula IV.
  • a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e.
  • the antisense strand and sense strand form an siRNA
  • the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-fluoro nucleotides the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 21 nucleotides in length and the nucleotides of the sense strand are modified such that, counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’
  • the antisense strand has the modification pattern represented by Formula V and the sense strand has the modification represented by Formula VI.
  • a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e.
  • the antisense strand and sense strand form an siRNA
  • the antisense strand is 23 nucleotides in length and wherein the nucleotides of the antisense strand are modified such that counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 21 nucleotides in length and the nucleotides of the sense strand are modified such that counting from the 5’ terminus of the sense strand, nucleo
  • the antisense strand has the modification pattern represented by Formula VII and the sense strand has the modification pattern represented by Formula VIII.
  • a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e.
  • the antisense strand and sense strand form an siRNA
  • the antisense strand is 23 nucleotides in length and wherein the nucleotides of the antisense strand are modified such that counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages ,and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 21 nucleotides in length and nucleotides of the sense strand are modified such that counting from the 5’ terminus of the sense strand, nucleo
  • the antisense strand has the modification pattern of Formula IX and the sense strand has the modification pattern of Formula X.
  • a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e.
  • the antisense strand and sense strand form an siRNA
  • the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-fluoro nucleotides the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoro nucleotides, nucleot
  • the antisense strand has the modification pattern represented by Formula V and the sense strand has the modification represented by Formula XI.
  • a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e.
  • the antisense strand and sense strand form an siRNA
  • the antisense strand is 23 nucleotides in length and wherein the nucleotides of the antisense strand are modified such that counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19,
  • the antisense strand has the modification pattern represented by Formula VII and the sense strand has the modification pattern represented by Formula XII.
  • a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e.
  • the antisense strand and sense strand form an siRNA
  • the antisense strand is 23 nucleotides in length and wherein the nucleotides of the antisense strand are modified such that counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages ,and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17,
  • the antisense strand has the modification pattern of Formula IX and the sense strand has the modification pattern of Formula XIII.
  • a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e.
  • the antisense strand and sense strand form an siRNA
  • the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-fluoro nucleotides the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 21 nucleotides in length and the nucleotides of the sense strand are modified such that, counting from the 5’ terminus of the sense strand, nucleotides 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-
  • a compound comprises an siRNA described herein.
  • a compound is selected from DT-000469, DT-000470, DT-000118, DT-000362, DT-000363, DT-000364, DT-000365, DT-000120, DT-000366, DT-000367, DT-000368, DT-000369, DT-000370, DT-000371, DT-000372, DT-000373, DT-000119, DT-000374, DT-000375, DT-000376, DT-000471, DT-000472, DT-000473, DT-000474, DT-000475, DT-000484, DT-000485, DT-000486, DT-000110, DT-000111, DT-000107, DT-000108,
  • a compound is selected from DT- 001373, DT-001374, DT-001375, and DT-001386.
  • the compound is DT-000469.
  • the compound is DT-000470.
  • the compound is DT-000118.
  • the compound is DT-000362.
  • the compound is DT-000363.
  • the compound is DT-000364.
  • the compound is DT-000365.
  • the compound is selected DT-000120.
  • the compound is DT-000366.
  • the compound is DT-000367.
  • the compound is DT-000368.
  • the compound is DT-000369. In embodiments, the compound is DT-000369. In embodiments, the compound is DT-000370. In embodiments, the compound is DT-000371. In embodiments, the compound is DT-000372. In embodiments, the compound is DT-000373. In embodiments, the compound is DT-000119. In embodiments, the compound is DT-000374. In embodiments, the compound is DT-000375. In embodiments, the compound is DT-000376. In embodiments, the compound is DT-000471. In embodiments, the compound is DT-000472. In embodiments, the compound is DT-000473. In embodiments, the compound is DT-000474.
  • the compound is DT-000475. In embodiments, the compound is DT-000484. In embodiments, the compound is DT-000485. In embodiments, the compound is DT-000486. In embodiments, the compound is DT-000110. In embodiments, the compound is DT-000111. In embodiments, the compound is DT-000107. In embodiments, the compound is DT-000108. In embodiments, the compound is DT-000490. In embodiments, the compound is DT-000491. In embodiments, the compound is DT-000492. In embodiments, the compound is DT-000495. In embodiments, the compound is DT-000496. In embodiments, the compound is DT-000497.
  • the compound is DT-000502. In embodiments, the compound is DT-000503. In embodiments, the compound is DT-000504. In embodiments, the compound is DT-000508. In embodiments, the compound is DT-000523. In embodiments, the compound is DT-000524. In embodiments, the compound is DT-000117. In embodiments, the compound is DT-000112. In embodiments, the compound is DT-000113. In embodiments, the compound is DT-000114. In embodiments, the compound is DT-000115. In embodiments, the compound is DT-000534. In embodiments, the compound is DT-000535. In embodiments, the compound is DT-000726.
  • the compound is DT-000727. In embodiments, the compound is DT-000734. In embodiments, the compound is DT-000782. In embodiments, the compound is DT-000783. In embodiments, the compound is DT-000784. In embodiments, the compound is DT-001373. In embodiments, the compound is DT-001374. In embodiments, the compound is DT-001375. In embodiments, the compound is DT-001386. In embodiments, a compound comprises an siRNA described herein, wherein each antisense strand has the modification pattern of Formula I, and each sense strand of has the modification pattern of Formula IV.
  • a compound comprises an siRNA described herein, wherein each antisense strand has the modification pattern of Formula V and each sense strand has the modification pattern of Formula VI. In embodiments, a compound comprises an siRNA described herein, wherein each antisense strand has the modification pattern of Formula VII and each sense strand has the modification pattern of Formula VIII. In embodiments, a compound comprises an siRNA described herein, wherein each antisense strand has the modification pattern of Formula IX and each sense strand has the modification pattern of Formula X.
  • a compound comprises an siRNA described herein, wherein each antisense strand has the modification pattern of Formula a compound comprises an siRNA described herein, wherein each antisense strand has the modification pattern of Formula IX and each sense strand has the modification pattern of Formula X and each sense strand has the modification pattern of Formula XIV.
  • a compound provided herein comprises a covalently linked ligand.
  • a compound provided herein comprises a ligand covalently linked to the antisense strand.
  • a compound provided herein comprises a ligand covalently linked to the sense strand.
  • the ligand comprises an uptake motif with one or more long chain fatty acids (LFCA).
  • a compound comprising an uptake motif has the structure (I) wherein A is a double-stranded nucleic acid and t is an integer from 1 to 5. In embodiments, A is the sense strand. In embodiments, A is the antisense strand.
  • L 3 and L 4 are independently a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO 2 -O-, -O-P(O)(S)-O-, -O-P(O)(R 25 )-O-, -O-P(S)(R 25 )-O-, -O-P(O)(NR 23 R 24 )-N-, -O-P(S)(NR 23 R 24 )-N-, -O-P(O)(NR 23 R 24 )-N-, -O-P
  • Each R 23 , R 24 and R 25 is independently hydrogen or unsubstituted C 1 -C 10 alkyl.
  • L 5 is -L 5A -L 5B -L 5C -L 5D -L 5E - and
  • L 6 is -L 6A -L 6B -L 6C -L 6D -L 6E -.
  • L 5A , L 5B , L 5C , L 5D , L 5E , L 6A , L 6B , L 6C , L 6D , and L 6E are independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, –C(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene.
  • R 1 and R 2 are independently unsubstituted C 1 -C 25 alkyl, wherein at least one of R 1 and R 2 is unsubstituted C9-C19 alkyl. In embodiments, R 1 and R 2 are independently unsubstituted C 1 -C 20 alkyl, wherein at least one of R 1 and R 2 is unsubstituted C 9 -C 19 alkyl.
  • R 3 is hydrogen, -NH 2 , -OH, -SH, -C(O)H, -C(O)NH 2 , -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • t is 1. In embodiments, t is 2.
  • t is 3. In embodiments, t is 4. In embodiments, t is 5. In embodiments, one L 3 is attached to a 3’ carbon of a nucleotide. In embodiments, one L 3 is attached to the 3’ carbon the 3’ terminal nucleotide of the sense strand. In embodiments, one L 3 is attached to the 3’ carbon of the 3’ terminal nucleotide of the antisense strand. In embodiments, one L 3 is attached to a 5’ carbon of a nucleotide. In embodiments, one L 3 is attached to the 5’ carbon of the 5’ terminal nucleotide of the sense strand.
  • one L 3 is attached to the 5’ carbon of the 5’ terminal nucleotide of the antisense strand. In embodiments, one L 3 is attached to a 2’ carbon of a nucleotide. In embodiments, one L 3 is attached to a 2’ carbon of a nucleotide of the sense strand. In embodiments, one L 3 is attached to a 2’ carbon of a nucleotide of the antisense strand. In embodiments, one L 3 is attached to a nucleobase. In embodiments, one L 3 is attached to a nucleobase of the sense strand. In embodiments, one L 3 is attached to a nucleobase of the antisense strand.
  • one L 3 is attached to a phosphate group at a 3’ carbon of a nucleotide. In embodiments, one L 3 is attached to a phosphate group at the 3’ carbon the 3’ terminal nucleotide of the sense strand. In embodiments, one L 3 is attached to a phosphate group at the 3’ carbon of the 3’ terminal nucleotide of the antisense strand. In embodiments, one L 3 is attached to a phosphate group at a 5’ carbon of a nucleotide. In embodiments, one L 3 is attached to a phosphate group at the 5’ carbon of the 5’ terminal nucleotide of the sense strand.
  • one L 3 is attached to a phosphate group at the 5’ carbon of the 5’ terminal nucleotide of the antisense strand. In embodiments, one L 3 is attached to a phosphate group at a 2’ carbon of a nucleotide. In embodiments, one L 3 is attached to a phosphate group at a 2’ carbon of a nucleotide of the sense strand. In embodiments, one L 3 is attached to a phosphate group a 2’ carbon of a nucleotide of the antisense strand.
  • L 3 is a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R 25 )-O-, -O-P(S)(R 25 )-O-, -O-P(O)(NR 23 R 24 )-N-, -O-P(S)(NR 23 R 24 )-N-, -O-P(O)(NR 23 R 24 )-N-, -O-P(O)(NR 23
  • L 3 is a bond. In embodiments, L 3 is -N(R 23 )-. In embodiments, L 3 is -O- or -S-. In embodiments, L 3 is -C(O)-. In embodiments, L 3 is -N(R 23 )C(O)- or -C(O)N(R 24 )-. In embodiments, L 3 is -N(R 23 )C(O)N(R 24 )-. In embodiments, L 3 is -C(O)O- or -OC(O)-. In embodiments, L 3 is -N(R 23 )C(O)O- or -OC(O)N(R 24 )-.
  • L 3 is -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R 25 )-O-, -O-P(O)(NR 23 R 24 )-N-, or -O-P(O)(NR 23 R 24 )-O-.
  • L 3 is -P(O)(NR 23 R 24 )-N-, -P(S)(NR 23 R 24 )-N-, -P(O)(NR 23 R 24 )-O-, or -P(S)(NR 23 R 24 )-O-.
  • L 3 is -S-S-.
  • L 3 is independently substituted or unsubstituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L 3 is independently substituted alkylene (e.g., C 1 -C 23 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, L 3 is independently unsubstituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • L 3 is independently unsubstituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • L 3 is independently substituted or unsubstituted C1-C23 alkylene. In embodiments, L 3 is independently substituted C 1 -C 23 alkylene. In embodiments, L 3 is independently unsubstituted C1-C23 alkylene. In embodiments, L 3 is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L 3 is independently substituted C1-C12 alkylene. In embodiments, L 3 is independently unsubstituted C 1 -C 12 alkylene. In embodiments, L 3 is independently substituted or unsubstituted C 1 -C 8 alkylene. In embodiments, L 3 is independently substituted C1-C8 alkylene.
  • L 3 is independently unsubstituted C1-C8 alkylene. In embodiments, L 3 is independently substituted or unsubstituted C 1 -C 6 alkylene. In embodiments, L 3 is independently substituted C 1 -C 6 alkylene. In embodiments, L 3 is independently unsubstituted C1-C6 alkylene. In embodiments, L 3 is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L 3 is independently substituted C 1 -C 4 alkylene. In embodiments, L 3 is independently unsubstituted C1-C4 alkylene. In embodiments, L 3 is independently substituted or unsubstituted ethylene.
  • L 3 is independently substituted ethylene. In embodiments, L 3 is independently unsubstituted ethylene. In embodiments, L 3 is independently substituted or unsubstituted methylene. In embodiments, L 3 is independently substituted methylene. In embodiments, L 3 is independently unsubstituted methylene. In embodiments, L 3 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • heteroalkylene e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered.
  • L 3 is independently substituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • L 3 is independently unsubstituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • L 3 is independently substituted or unsubstituted 2 to 23 membered heteroalkylene.
  • L 3 is independently substituted 2 to 23 membered heteroalkylene. In embodiments, L 3 is independently unsubstituted 2 to 23 membered heteroalkylene. In embodiments, L 3 is independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 3 is independently substituted 2 to 8 membered heteroalkylene. In embodiments, L 3 is independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 3 is independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 3 is independently substituted 2 to 6 membered heteroalkylene.
  • L 3 is independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 3 is independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L 3 is independently substituted 4 to 6 membered heteroalkylene. In embodiments, L 3 is independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L 3 is independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L 3 is independently substituted 2 to 3 membered heteroalkylene. In embodiments, L 3 is independently unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L 3 is independently unsubstituted 2 to 3 membered heteroalkylene.
  • L 3 is independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L 3 is independently substituted 4 to 5 membered heteroalkylene. In embodiments, L 3 is independently unsubstituted 4 to 5 membered heteroalkylene.
  • L 4 is a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 ) -, -C(O)O-, -OC(O) -, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO 2 -O-, -O-P(O)(S)-O-, -O-P(O)(R 25 )-O-, -O-P(S)(R 25 )-O-, -O-P(O)(NR 23 R 24 )-N-, -O-P(S)(NR 23 R 24 )-N-, -O-P(O)(NR 23 R 24 )-N-, -O-P(O
  • L 4 is a bond. In embodiments, L 4 is -N(R 23 )-. In embodiments, L 4 is -O- or -S-. In embodiments, L 4 is -C(O)-. In embodiments, L 4 is -N(R 23 )C(O)- or -C(O)N(R 24 )-. In embodiments, L 4 is -N(R 23 )C(O)N(R 24 )-. In embodiments, L 4 is -C(O)O- or -OC(O)-. In embodiments, L 4 is -N(R 23 )C(O)O- or -OC(O)N(R 24 )-.
  • L 4 is -OPO 2 -O-, -O-P(O)(S)-O-, -O-P(O)(R 25 )-O-, -O-P(O)(NR 23 R 24 )-N-, or -O-P(O)(NR 23 R 24 )-O-.
  • L 4 is -P(O)(NR 23 R 24 )-N-,-P(S)(NR 23 R 24 )-N-, -P(O)(NR 23 R 24 )-O- or -P(S)(NR 23 R 24 )-O-.
  • L 4 is -S-S-.
  • L 4 is independently substituted or unsubstituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L 4 is independently substituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L 4 is independently unsubstituted alkylene (e.g., C 1 -C 23 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • L 4 is independently substituted or unsubstituted C 1 -C 23 alkylene. In embodiments, L 4 is independently substituted C1-C23 alkylene. In embodiments, L 4 is independently unsubstituted C1-C23 alkylene. In embodiments, L 4 is independently substituted or unsubstituted C 1 -C 12 alkylene. In embodiments, L 4 is independently substituted C 1 -C 12 alkylene. In embodiments, L 4 is independently unsubstituted C1-C12 alkylene. In embodiments, L 4 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L 4 is independently substituted C 1 -C 8 alkylene.
  • L 4 is independently unsubstituted C1-C8 alkylene. In embodiments, L 4 is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L 4 is independently substituted C1-C6 alkylene. In embodiments, L 4 is independently unsubstituted C 1 -C 6 alkylene. In embodiments, L 4 is independently substituted or unsubstituted C 1 -C 4 alkylene. In embodiments, L 4 is independently substituted C1-C4 alkylene. In embodiments, L 4 is independently unsubstituted C1-C4 alkylene. In embodiments, L 4 is independently substituted or unsubstituted ethylene.
  • L 4 is independently substituted ethylene. In embodiments, L 4 is independently unsubstituted ethylene. In embodiments, L 4 is independently substituted or unsubstituted methylene. In embodiments, L 4 is independently substituted methylene. In embodiments, L 4 is independently unsubstituted methylene. In embodiments, L 4 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • heteroalkylene e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered.
  • L 4 is independently substituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • L 4 is independently unsubstituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • L 4 is independently substituted or unsubstituted 2 to 23 membered heteroalkylene.
  • L 4 is independently substituted 2 to 23 membered heteroalkylene. In embodiments, L 4 is independently unsubstituted 2 to 23 membered heteroalkylene. In embodiments, L 4 is independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 4 is independently substituted 2 to 8 membered heteroalkylene. In embodiments, L 4 is independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 4 is independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 4 is independently substituted 2 to 6 membered heteroalkylene.
  • L 4 is independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 4 is independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L 4 is independently substituted 4 to 6 membered heteroalkylene. In embodiments, L 4 is independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L 4 is independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L 4 is independently substituted 2 to 3 membered heteroalkylene. In embodiments, L 4 is independently unsubstituted 2 to 3 membered heteroalkylene.
  • L 4 is independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L 4 is independently substituted 4 to 5 membered heteroalkylene. In embodiments, L 4 is independently unsubstituted 4 to 5 membered heteroalkylene.
  • R 23 is independently hydrogen or unsubstituted alkyl (e.g., C 1 -C 23 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 23 is independently hydrogen. In embodiments, R 23 is independently unsubstituted C1-C23 alkyl.
  • R 23 is independently hydrogen or unsubstituted C1-C12 alkyl. In embodiments, R 23 is independently hydrogen or unsubstituted C 1 -C 10 alkyl. In embodiments, R 23 is independently hydrogen or unsubstituted C1-C8 alkyl. In embodiments, R 23 is independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R 23 is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 23 is independently hydrogen or unsubstituted C 1 -C 2 alkyl.
  • R 24 is independently hydrogen or unsubstituted alkyl (e.g., C1-C24, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 24 is independently hydrogen. In embodiments, R 24 is independently unsubstituted C 1 -C 24 alkyl. In embodiments, R 24 is independently hydrogen or unsubstituted C 1 -C 12 alkyl. In embodiments, R 24 is independently hydrogen or unsubstituted C1-C10 alkyl. In embodiments, R 24 is independently hydrogen or unsubstituted C1-C8 alkyl. In embodiments, R 24 is independently hydrogen or unsubstituted C1-C6 alkyl.
  • R 24 is independently hydrogen or unsubstituted alkyl (e.g., C1-C24, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 24 is independently hydrogen
  • R 24 is independently hydrogen or unsubstituted C 1 -C 4 alkyl. In embodiments, R 24 is independently hydrogen or unsubstituted C1-C2 alkyl.
  • R 25 is independently hydrogen or unsubstituted alkyl (e.g., C1-C25, C1-C12, C1-C8, C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 25 is independently hydrogen. In embodiments, R 25 is independently unsubstituted C1-C25 alkyl. In embodiments, R 25 is independently hydrogen or unsubstituted C1-C12 alkyl.
  • R 25 is independently hydrogen or unsubstituted C1-C10 alkyl. In embodiments, R 25 is independently hydrogen or unsubstituted C 1 -C 8 alkyl. In embodiments, R 25 is independently hydrogen or unsubstituted C 1 -C 6 alkyl. In embodiments, R 25 is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 25 is independently hydrogen or unsubstituted C1-C2 alkyl.
  • L 3 and L 4 are independently a bond, -NH-, -O-,-C(O)-, -C(O)O-, -OC(O)-, -OPO 2 -O- -O-P(O)(S)-O-, -O-P(O)(CH 3 )-O-, -O-P(S)(CH 3 )-O-, -O-P(O)(N(CH3)2)-N-, -O-P(O)(N(CH3)2)-O-, -O-P(S)(N(CH3)2)-N-, -O-P(S)(N(CH3)2)-O-, -P(O)(N(CH3)2)-N-, -P(O)(N(CH3)2)-O-, -P(O)(N(CH3)2)-N-, -P(O)(N(CH3)2)-O-, -P(O)(N(CH3)2)-N-
  • L 3 is independently a bond, -NH-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(CH3)-O-, -O-P(S)(CH3)-O-, -O-P(O)(N(CH3)2)-N-, -O-P(O)(N(CH3)2)-O-, -O-P(S)(N(CH 3 ) 2 )-N-, -O-P(S)(N(CH 3 ) 2 )-O-, - P(O)(N(CH 3 ) 2 )-N-, -P(O)(N(CH 3 ) 2 )-O-, -P(S)(N(CH3)2)-N-, -P(S)(N(CH3)2)-O-, substituted or
  • L 4 is independently a bond, -NH-, -O-, -C(O)-, -C(O)O-, -OC(O) -, -OPO 2 -O-, -O-P(O)(S)-O-, -O-P(O)(CH 3 )-O-, -O-P(S)(CH 3 )-O-, -O-P(O)(N(CH 3 ) 2 )-N-, -O-P(O)(N(CH 3 ) 2 )-O-, -O-P(S)(N(CH 3 ) 2 )-N-, -O-P(S)(N(CH 3 ) 2 )-O-, -P(O)(N(CH3)2)-N-, -P(O)(N(CH3)2)-O-, -P(S)(N(CH3)2)-O-, -P(S)(N(CH3)2)-O-
  • L 3 is independently . In embodiments, L 3 is independently -OPO2-O-. In embodiments, L 3 is independently -O-P(O)(S)-O-. In embodiments, L 3 is independently -O-. In embodiments, L 3 is independently -S-. In embodiments, L 4 is independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In embodiments, L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-.
  • L 7 is independently substituted or unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • L 7 is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • L 7 is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • L 4 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • L 4 is independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • L 4 is independently oxo-substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • L 4 is independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • L 4 is independently -L 7 -NH-C(O)-; and L 7 is independently substituted or unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C1-C4, or C1-C2).
  • L 4 is independently -L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C 1 -C 4 , or C 1 -C 2 ). In embodiments, L 7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • alkylene e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2
  • L 7 is independently substituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, L 7 is independently unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, L 7 is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L 7 is independently substituted C1-C20 alkylene.
  • L 7 is independently hydroxy(OH)-substituted C 1 -C 20 alkylene. In embodiments, L 7 is independently hydroxymethyl-substituted C1-C20 alkylene. In embodiments, L 7 is independently unsubstituted C1-C20 alkylene. In embodiments, L 7 is independently substituted or unsubstituted C 1 -C 12 alkylene. In embodiments, L 7 is independently substituted C 1 -C 12 alkylene. In embodiments, L 7 is independently hydroxy(OH)-substituted C1-C12 alkylene. In embodiments, L 7 is independently hydroxymethyl-substituted C1-C12 alkylene.
  • L 7 is independently unsubstituted C 1 -C 12 alkylene. In embodiments, L 7 is independently substituted or unsubstituted C 1 -C 8 alkylene. In embodiments, L 7 is independently substituted C1-C8 alkylene. In embodiments, L 7 is independently hydroxy(OH)-substituted C1-C8 alkylene. In embodiments, L 7 is independently hydroxymethyl-substituted C 1 -C 8 alkylene. In embodiments, L 7 is independently unsubstituted C1-C8 alkylene. In embodiments, L 7 is independently substituted or unsubstituted C1-C6 alkylene.
  • L 7 is independently substituted C1-C6 alkylene. In embodiments, L 7 is independently hydroxy(OH)-substituted C 1 -C 6 alkylene. In embodiments, L 7 is independently hydroxymethyl-substituted C1-C6 alkylene. In embodiments, L 7 is independently unsubstituted C1-C6 alkylene. In embodiments, L 7 is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L 7 is independently substituted C 1 -C 4 alkylene. In embodiments, L 7 is independently hydroxy(OH)-substituted C1-C4 alkylene.
  • L 7 is independently hydroxymethyl-substituted C1-C4 alkylene. In embodiments, L 7 is independently unsubstituted C 1 -C 4 alkylene. In embodiments, L 7 is independently substituted or unsubstituted C 1 -C 2 alkylene. In embodiments, L 7 is independently substituted C 1 -C 2 alkylene. In embodiments, L 7 is independently hydroxy(OH)-substituted C1-C2 alkylene. In embodiments, L 7 is independently hydroxymethyl-substituted C1-C2 alkylene. In embodiments, L 7 is independently unsubstituted C 1 -C 2 alkylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C 1 -C 4 , or C 1 -C 2 ).
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted C1-C8 alkylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently substituted C1-C8 alkylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently hydroxy(OH)-substituted C 1 -C 8 alkylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently hydroxymethyl-substituted C1-C8 alkylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently unsubstituted C 1 -C 8 alkylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted C3-C8 alkylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently substituted C 3 -C 8 alkylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently hydroxy(OH)-substituted C3-C8 alkylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently hydroxymethyl-substituted C 3 -C 8 alkylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently unsubstituted C3-C8 alkylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted C 5 -C 8 alkylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently substituted C5-C8 alkylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently hydroxy(OH)-substituted C 5 -C 8 alkylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently hydroxymethyl-substituted C5-C8 alkylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently unsubstituted C5-C8 alkylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted octylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently substituted octylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently hydroxy(OH)-substituted octylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently unsubstituted octylene.
  • L 4 is independently -L 7 -NH-C(O)- and L 7 is independently hydroxy(OH)-substituted octylene. In embodiments, L 4 is independently -L 7 -NH-C(O)- and L 7 is independently hydroxymethyl-substituted octylene. In embodiments, L 4 is independently -L 7 -NH-C(O)- and L 7 is independently unsubstituted octylene. In embodiments, L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted heptylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently substituted heptylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently hydroxy(OH)-substituted heptylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently unsubstituted heptylene.
  • L 4 is independently -L 7 -NH-C(O)- and L 7 is independently hydroxy(OH)-substituted heptylene. In embodiments, L 4 is independently -L 7 -NH-C(O)- and L 7 is independently hydroxymethyl-substituted heptylene. In embodiments, L 4 is independently -L 7 -NH-C(O)- and L 7 is independently unsubstituted heptylene. In embodiments, L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted hexylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently substituted hexylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently hydroxy(OH)-substituted hexylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently unsubstituted hexylene.
  • L 4 is independently -L 7 -NH-C(O)- and L 7 is independently hydroxy(OH)-substituted hexylene. In embodiments, L 4 is independently -L 7 -NH-C(O)- and L 7 is independently hydroxymethyl-substituted hexylene. In embodiments, L 4 is independently -L 7 -NH-C(O)- and L 7 is independently unsubstituted hexylene. In embodiments, L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted pentylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently substituted pentylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently hydroxy(OH)-substituted pentylene.
  • L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; and L 7 is independently unsubstituted pentylene.
  • L 4 is independently -L 7 -NH-C(O)- and L 7 is independently hydroxy(OH)-substituted pentylene. In embodiments, L 4 is independently -L 7 -NH-C(O)- and L 7 is independently hydroxymethyl-substituted pentylene. In embodiments, L 4 is independently -L 7 -NH-C(O)- and L 7 is independently unsubstituted pentylene. In embodiments, L 4 is independently . In embodiments, L 4 is independently . In embodiments, L 4 is independently . In embodiments, L 4 is independently . In embodiments, L 4 is independently . In embodiments, L 4 is independently . In embodiments, L 4 is independently . In embodiments, L 4 is independently . In embodiments, L 4 is independently . In embodiments, L 4 is independently .
  • L 4 is independently . In embodiments, L 4 is independently . , . In embodiments, -L 3 -L 4 - is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-. In embodiments, L 7 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • heteroalkylene e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered.
  • L 7 is independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • L 7 is independently oxo-substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • L 7 is independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • L 7 is independently substituted or unsubstituted heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • L 7 is independently substituted heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • L 7 is independently oxo-substituted heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • L 7 is independently unsubstituted heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L 7 is independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L 7 is independently substituted 2 to 20 membered heteroalkylene. In embodiments, L 7 is independently oxo-substituted 2 to 20 membered heteroalkylene. In embodiments, L 7 is independently unsubstituted 2 to 20 membered heteroalkylene.
  • L 7 is independently substituted or unsubstituted 2 to 12 membered heteroalkylene. In embodiments, L 7 is independently substituted 2 to 12 membered heteroalkylene. In embodiments, L 7 is independently oxo-substituted 2 to 12 membered heteroalkylene. In embodiments, L 7 is independently unsubstituted 2 to 12 membered heteroalkylene. In embodiments, L 7 is independently substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L 7 is independently substituted 2 to 10 membered heteroalkylene. In embodiments, L 7 is independently oxo-substituted 2 to 10 membered heteroalkylene.
  • L 7 is independently unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L 7 is independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 7 is independently substituted 2 to 8 membered heteroalkylene. In embodiments, L 7 is independently oxo-substituted 2 to 8 membered heteroalkylene. In embodiments, L 7 is independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 7 is independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 7 is independently substituted 2 to 6 membered heteroalkylene.
  • L 7 is independently oxo-substituted 2 to 6 membered heteroalkylene. In embodiments, L 7 is independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 7 is independently substituted or unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L 7 is independently substituted 2 to 4 membered heteroalkylene. In embodiments, L 7 is independently oxo-substituted 2 to 4 membered heteroalkylene. In embodiments, L 7 is independently unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L 7 is independently substituted or unsubstituted 2 to 20 membered heteroalkenylene.
  • L 7 is independently substituted 2 to 20 membered heteroalkenylene. In embodiments, L 7 is independently oxo-substituted 2 to 20 membered heteroalkenylene. In embodiments, L 7 is independently unsubstituted 2 to 20 membered heteroalkenylene. In embodiments, L 7 is independently substituted or unsubstituted 2 to 12 membered heteroalkenylene. In embodiments, L 7 is independently substituted 2 to 12 membered heteroalkenylene. In embodiments, L 7 is independently oxo-substituted 2 to 12 membered heteroalkenylene. In embodiments, L 7 is independently unsubstituted 2 to 12 membered heteroalkenylene.
  • L 7 is independently substituted or unsubstituted 2 to 10 membered heteroalkenylene. In embodiments, L 7 is independently substituted 2 to 10 membered heteroalkenylene. In embodiments, L 7 is independently oxo-substituted 2 to 10 membered heteroalkenylene. In embodiments, L 7 is independently unsubstituted 2 to 10 membered heteroalkenylene. In embodiments, L 7 is independently substituted or unsubstituted 2 to 8 membered heteroalkenylene. In embodiments, L 7 is independently substituted 2 to 8 membered heteroalkenylene. In embodiments, L 7 is independently oxo-substituted 2 to 8 membered heteroalkenylene.
  • L 7 is independently unsubstituted 2 to 8 membered heteroalkenylene. In embodiments, L 7 is independently substituted or unsubstituted 2 to 6 membered heteroalkenylene. In embodiments, L 7 is independently substituted 2 to 6 membered heteroalkenylene. In embodiments, L 7 is independently oxo-substituted 2 to 6 membered heteroalkenylene. In embodiments, L 7 is independently unsubstituted 2 to 6 membered heteroalkenylene. In embodiments, L 7 is independently substituted or unsubstituted 2 to 4 membered heteroalkenylene. In embodiments, L 7 is independently substituted 2 to 4 membered heteroalkenylene.
  • L 7 is independently oxo-substituted 2 to 4 membered heteroalkenylene. In embodiments, L 7 is independently unsubstituted 2 to 4 membered heteroalkenylene. In embodiments, -L 3 -L 4 - is independently -O-L 7 -NH-C(O)- or -O-L 7 -C(O)-NH-. In embodiments, L 7 is independently substituted or unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C1-C8, C1-C6, C1-C4, or C1-C2).
  • alkylene e.g., C 1 -C 20 , C 1 -C 12 , C1-C8, C1-C6, C1-C4, or C1-C2
  • -L 3 -L 4 - is independently -O-L 7 -NH-C(O)- or -O-L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • -L 3 -L 4 - is independently -O-L 7 -NH-C(O)-; and L 7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • -L 3 -L 4 - is independently -O-L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • L 3 -L 4 - is independently -O-L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted C1-C8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -C(O)-NH-; and L 7 is independently substituted C 1 -C 8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -C(O)-NH-; and L 7 is independently hydroxy(OH)-substituted C1-C8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -C(O)- NH-and L 7 is independently hydroxymethyl-substituted C 1 -C 8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -C(O)-NH-; and L 7 is independently unsubstituted C1-C8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted C 3 -C 8 alkylene.
  • -L 3 -L 4 - is independently O-L 7 -C(O)-NH-; and L 7 is independently substituted C 3 -C 8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -C(O)-NH-; and L 7 is independently hydroxy(OH)-substituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -C(O)-NH- and L 7 is independently hydroxymethyl-substituted C 3 -C 8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -C(O)-NH-; and L 7 is independently unsubstituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted C 5 -C 8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -C(O)-NH-; and L 7 is independently substituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -C(O)-NH-; and L 7 is independently hydroxy(OH)-substituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -C(O)-NH- and L 7 is independently hydroxymethyl-substituted C 5 -C 8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -C(O)-NH-; and L 7 is independently unsubstituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -NH-C(O)-; and L 7 is independently substituted or unsubstituted C 1 -C 8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -NH-C(O)-; and L 7 is independently substituted C 1 -C 8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -NH-C(O)-; and L 7 is independently hydroxy(OH)-substituted C1-C8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -NH-C(O)-; and L 7 is independently hydroxymethyl-substituted C 1 -C 8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -NH-C(O)-; and L 7 is independently unsubstituted C1-C8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -NH-C(O)-; and L 7 is independently substituted or unsubstituted C 3 -C 8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -NH-C(O)-; and L 7 is independently substituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -NH-C(O)-; and L 7 is independently hydroxy(OH)-substituted C 3 -C 8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -NH-C(O)-; and L 7 is independently hydroxymethyl-substituted C 3 -C 8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -NH-C(O)-; and L 7 is independently unsubstituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -NH-C(O)-; and L 7 is independently substituted or unsubstituted C 5 -C 8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -NH-C(O)-; and L 7 is independently substituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -NH-C(O)-; and L 7 is independently hydroxy(OH)-substituted C 5 -C 8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -NH-C(O)-; and L 7 is independently hydroxymethyl-substituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently -O-L 7 -NH-C(O)-; and L 7 is independently unsubstituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently , embodiments, -L 3 -L 4 - is independently . In embodiments, -L 3 -L 4 - is independently . In embodiments, -L 3 -L 4 - is independently . In embodiments, -L 3 -L 4 - is independently -OPO 2 -O-L 7 -NH-C(O)-, -OP(O)(S)-O-L 7 -NH-C(O)-, -OPO2-O-L 7 -C(O)-NH-or -OP(O)(S)-O-L 7 -C(O)-NH-.
  • L 7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -NH-C(O)- or -OP(O)(S)-O-L 7 -NH-C(O)-; and L 7 is independently substituted or unsubstituted alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -NH-C(O)-; and L 7 is independently substituted or unsubstituted alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -NH-C(O)-; and L 7 is independently substituted or unsubstituted alkylene.
  • -L 3 -L 4 - is independently -OPO 2 -O-L 7 -C(O)-NH- or -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted alkylene.
  • -L 3 -L 4 - is independently -OPO 2 -O-L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -NH-C(O)- or -OPO2-O-L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -NH-C(O)-; and L 7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • L 7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • -L 3 -L 4 - is independently -OPO 2 -O-L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -NH-C(O)- or -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • alkylene e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 .
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -NH-C(O)-; and L 7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • L 7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted C1-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO 2 -O-L 7 -C(O)-NH-; and L 7 is independently substituted C 1 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -C(O)-NH-; and L 7 is independently hydroxy(OH)-substituted C1-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO 2 -O-L 7 -C(O)-NH-; and L 7 is independently hydroxymethyl-substituted C 1 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OPO 2 -O-L 7 -C(O)-NH-; and L 7 is independently unsubstituted C1-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted C 1 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently substituted C1-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently hydroxy(OH)-substituted C 1 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently hydroxymethyl-substituted C1-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently unsubstituted C 1 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OPO 2 -O-L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -C(O)-NH-; and L 7 is independently substituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO 2 -O-L 7 -C(O)-NH-; and L 7 is independently hydroxy(OH)-substituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -C(O)-NH-; and L 7 is independently hydroxymethyl-substituted C 3 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OPO 2 -O-L 7 -C(O)-NH-; and L 7 is independently unsubstituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted C 3 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently substituted C 3 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently hydroxy(OH)-substituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently hydroxymethyl-substituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently unsubstituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO 2 -O-L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -C(O)-NH-; and L 7 is independently substituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -C(O)-NH-; and L 7 is independently hydroxy(OH)-substituted C 5 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -C(O)-NH-; and L 7 is independently hydroxymethyl-substituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -C(O)-NH-; and L 7 is independently unsubstituted C 5 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently substituted or unsubstituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently substituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently hydroxy(OH)-substituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently hydroxymethyl-substituted C 5 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -C(O)-NH-; and L 7 is independently unsubstituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -NH-C(O)-; and L 7 is independently substituted or unsubstituted C 1 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OPO 2 -O-L 7 -NH-C(O)-; and L 7 is independently substituted C 1 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -NH-C(O)-; and L 7 is independently hydroxy(OH)-substituted C1-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO 2 -O-L 7 -NH-C(O)-; and L 7 is independently hydroxymethyl-substituted C 1 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -NH-C(O)-; and L 7 is independently unsubstituted C1-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -NH-C(O)-; and L 7 is independently substituted or unsubstituted C1-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -NH-C(O)-; and L 7 is independently substituted C1-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S) 2 -O-L 7 -NH-C(O)-; and L 7 is independently hydroxy(OH)-substituted C 1 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -NH-C(O)-; and L 7 is independently hydroxymethyl-substituted C1-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -NH-C(O)-; and L 7 is independently unsubstituted C 1 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -NH-C(O)-; and L 7 is independently substituted or unsubstituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO 2 -O-L 7 -NH-C(O)-; and L 7 is independently substituted C 3 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -NH-C(O)-; and L 7 is independently hydroxy(OH)-substituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -NH-C(O)-; and L 7 is independently hydroxymethyl-substituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO 2 -O-L 7 -NH-C(O)-; and L 7 is independently unsubstituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -NH-C(O)-; and L 7 is independently substituted or unsubstituted C 3 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -NH-C(O)-; and L 7 is independently substituted C 3 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -NH-C(O)-; and L 7 is independently hydroxy(OH)-substituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -NH-C(O)-; and L 7 is independently hydroxymethyl-substituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -NH-C(O)-; and L 7 is independently unsubstituted C3-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO 2 -O-L 7 -NH-C(O)-; and L 7 is independently substituted or unsubstituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -NH-C(O)-; and L 7 is independently substituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO 2 -O-L 7 -NH-C(O)-; and L 7 is independently hydroxy(OH)-substituted C 5 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -NH-C(O)-; and L 7 is independently hydroxymethyl-substituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently -OPO2-O-L 7 -NH-C(O)-; and L 7 is independently unsubstituted C 5 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -NH-C(O)-; and L 7 is independently substituted or unsubstituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -NH-C(O)-; and L 7 is independently substituted C 5 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -NH-C(O)-; and L 7 is independently hydroxy(OH)-substituted C5-C8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -NH-C(O)-; and L 7 is independently hydroxymethyl-substituted C 5 -C 8 alkylene.
  • -L 3 -L 4 - is independently -OP(O)(S)-O-L 7 -NH-C(O)-; and L 7 is independently unsubstituted C5-C8 alkylene.
  • -L 3 -L 4 - is attached to a 3’ carbon of a nucleotide of the sense strand. In embodiments, -L 3 -L 4 - is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand. In embodiments, -L 3 -L 4 - is attached to a 3’ carbon of the antisense sense strand. In embodiments, -L 3 -L 4 - is attached to the 3’ carbon of the 3’ terminal nucleotide of the antisense sense strand. In embodiments, -L 3 -L 4 - is attached to a 5’ carbon of a nucleotide of the sense strand.
  • -L 3 -L 4 - is attached to the 5’ carbon of the 5’ terminal nucleotide of the sense strand. In embodiments, -L 3 -L 4 - is attached to a 5’ carbon of a nucleotide of the antisense strand. In embodiments, -L 3 -L 4 - is attached to the 5’ carbon of the 5’ terminal nucleotide of the antisense strand. In embodiments, -L 3 -L 4 - is attached to a 2’ carbon of a nucleotide of the sense strand. In embodiments, -L 3 -L 4 - is attached to a 2’ carbon of a nucleotide of the antisense strand.
  • -L 3 -L 4 - is attached to a nucleobase of the sense strand. In embodiments, -L 3 -L 4 - is attached to a nucleobase of the antisense strand. , . In embodiments, -L 3 -L 4 - is independently , , . embodiments, -L 3 -L 4 - is independently embodiments, -L 3 -L 4 - is independently , or . embodiments, -L 3 -L 4 - is independently
  • -L 3 -L 4 - is independently , and is attached to the 3’ carbon of the 3’ terminal nucleotide of the antisense strand.
  • -L 3 -L 4 - is independently that is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand.
  • -L 3 -L 4 - is independently that is attached to the 3’ carbon of the 3’ terminal nucleotide of the antisense strand.
  • -L 3 -L 4 - is independently , or that is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand.
  • -L 3 -L 4 - is independently that is attached to the 3’ carbon of the 3’ terminal nucleotide of the antisense strand. In embodiments, an -L 3 -L 4 - is independently , and is attached to the 5’ carbon of the 5’ terminal nucleotide of the sense strand. In embodiments, an -L 3 -L 4 - is independently , and is attached to the 5’ carbon of the 5’ terminal nucleotide of the antisense strand. In embodiments, an -L 3 -L 4 - is independently that is attached to the 5’ carbon of the 5’ terminal nucleotide of the sense strand.
  • an -L 3 -L 4 - is independentl y that is attached to the 5’ carbon of the 5’ terminal nucleotide of the antisense strand. In embodiments, an -L 3 -L 4 - is independently at is attached to 5’ carbon of the 5’ terminal nucleotide of the sense strand. In embodiments, an -L 3 -L 4 - is independently at is attached to the 5’ carbon of the 5’ terminal nucleotide of the antisense strand. In embodiments, an -L 3 -L 4 - is independently is attached to a nucleobase of the sense strand.
  • an -L 3 -L 4 - is independently is attached to a nucleobase of the sense strand. In embodiments, an -L 3 -L 4 - is independently attached to a nucleobase of the antisense strand. In embodiments, -L 3 -L 4 - is independently
  • -L 3 -L 4 - is independently that is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand. In embodiments, -L 3 -L 4 - is independently that is attached to the 3’ carbon of the 3’ terminal nucleotide of the antisense strand. In embodiments, -L 3 -L 4 - is independently that is attached to the 5’ carbon of the 5’ terminal nucleotide of the sense strand. In embodiments, -L 3 -L 4 - is independently that is attached to the 5’ carbon of the 5’ terminal nucleotide of the antisense strand.
  • -L 3 -L 4 - is independently that is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand. In embodiments, -L 3 -L 4 - is independently that is attached to the 3’ carbon of the 3’ terminal nucleotide of the antisense strand. In embodiments, -L 3 -L 4 - is independently that is attached to the 5’ carbon of the 5’ terminal nucleotide of the sense strand. In embodiments, -L 3 -L 4 - is independently that is attached to the 5’ carbon of the 5’ terminal nucleotide of the antisense strand.
  • -L 3 -L 4 - is independently attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand. In embodiments, -L 3 -L 4 - is independently attached to the 3’ carbon of the 3’ terminal nucleotide of the antisense strand. In embodiments, -L 3 -L 4 - is independently and is attached to the 5’ carbon of the 5’ terminal nucleotide of the sense strand. In embodiments, -L 3 -L 4 - is independently and is attached to the 5’ carbon of the 5’ terminal nucleotide of the antisense strand.
  • -L 3 -L 4 - is independently and is attached to a 2’ carbon of a nucleotide of the sense strand. In embodiments, -L 3 -L 4 - is independently and is attached to a 2’ carbon of a nucleotide of the antisense strand. In embodiments, -L 3 -L 4 - is independently and is attached to a 2’ carbon of a nucleotide of the sense strand. In embodiments, -L 3 -L 4 - is independently is attached to a 2’ carbon of a nucleotide of the antisense strand. In embodiments, -L 3 -L 4 - is independently is attached to a nucleobase of the sense strand.
  • -L 3 -L 4 - is independently is attached to a nucleobase of the antisense strand.
  • R 3 is independently hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH 2 , -NHC(O)H, -NHC(O)OH, -NHC(O)NH 2 , -C(O)OH, -OC(O)H, -N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is independently hydrogen. In embodiments, R 3 is independently -NH2. In embodiments, R 3 is independently -OH. In embodiments, R 3 is independently -SH. In embodiments, R 3 is independently -C(O)H. In embodiments, R 3 is independently -C(O)NH 2 . In embodiments, R 3 is independently -NHC(O)H. In embodiments, R 3 is independently -NHC(O)OH. In embodiments, R 3 is independently -NHC(O)NH2. In embodiments, R 3 is independently -C(O)OH. In embodiments, R 3 is independently -OC(O)H. In embodiments, R 3 is independently -N3.
  • R 3 is independently substituted or unsubstituted alkyl (e.g., C 1 -C 20 , C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 3 is independently substituted or unsubstituted C1-C20 alkyl. In embodiments, R 3 is independently substituted C1-C20 alkyl. In embodiments, R 3 is independently unsubstituted C 1 -C 20 alkyl. In embodiments, R 3 is independently substituted or unsubstituted C1-C12 alkyl. In embodiments, R 3 is independently substituted C1-C12 alkyl.
  • R 3 is independently substituted C1-C12 alkyl.
  • R 3 is independently unsubstituted C1-C12 alkyl. In embodiments, R 3 is independently substituted or unsubstituted C 1 -C 8 alkyl. In embodiments, R 3 is independently substituted C 1 -C 8 alkyl. In embodiments, R 3 is independently unsubstituted C1-C8 alkyl. In embodiments, R 3 is independently substituted or unsubstituted C1-C6 alkyl. In embodiments, R 3 is independently substituted C1-C6 alkyl. In embodiments, R 3 is independently unsubstituted C 1 -C 6 alkyl. In embodiments, R 3 is independently substituted or unsubstituted C1-C4 alkyl.
  • R 3 is independently substituted C1-C4 alkyl. In embodiments, R 3 is independently unsubstituted C1-C4 alkyl. In embodiments, R 3 is independently substituted or unsubstituted ethyl. In embodiments, R 3 is independently substituted ethyl. In embodiments, R 3 is independently unsubstituted ethyl. In embodiments, R 3 is independently substituted or unsubstituted methyl. In embodiments, R 3 is independently substituted methyl. In embodiments, R 3 is independently unsubstituted methyl. In embodiments, L 6 is independently -NHC(O)-. In embodiments, L 6 is independently -C(O)NH-.
  • L 6 is independently substituted or unsubstituted alkylene. In embodiments, L 6 is independently substituted or unsubstituted heteroalkylene. In embodiments, L 6 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L 6 is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • alkylene e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • L 6 is independently unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • L 6 is independently substituted or unsubstituted C1-C20 alkylene.
  • L 6 is independently substituted C1-C20 alkylene.
  • L 6 is independently unsubstituted C 1 -C 20 alkylene.
  • L 6 is independently substituted or unsubstituted C 1 -C 12 alkylene.
  • L 6 is independently substituted C 1 -C 12 alkylene.
  • L 6 is independently unsubstituted C1-C12 alkylene. In embodiments, L 6 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L 6 is independently substituted C 1 -C 8 alkylene. In embodiments, L 6 is independently unsubstituted C1-C8 alkylene. In embodiments, L 6 is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L 6 is independently substituted C1-C6 alkylene. In embodiments, L 6 is independently unsubstituted C 1 -C 6 alkylene. In embodiments, L 6 is independently substituted or unsubstituted C1-C4 alkylene.
  • L 6 is independently substituted C1-C4 alkylene. In embodiments, L 6 is independently unsubstituted C 1 -C 4 alkylene. In embodiments, L 6 is independently substituted or unsubstituted ethylene. In embodiments, L 6 is independently substituted ethylene. In embodiments, L 6 is independently unsubstituted ethylene. In embodiments, L 6 is independently substituted or unsubstituted methylene. In embodiments, L 6 is independently substituted methylene. In embodiments, L 6 is independently unsubstituted methylene.
  • L 6 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • L 6 is independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • L 6 is independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L 6 is independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L 6 is independently substituted 2 to 20 membered heteroalkylene. In embodiments, L 6 is independently unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L 6 is independently substituted or unsubstituted 2 to 8 membered heteroalkylene.
  • heteroalkylene e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered. In embodiments, L 6 is independently substituted or unsubstituted 2 to 20
  • L 6 is independently substituted 2 to 8 membered heteroalkylene. In embodiments, L 6 is independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 6 is independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 6 is independently substituted 2 to 6 membered heteroalkylene. In embodiments, L 6 is independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 6 is independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L 6 is independently substituted 4 to 6 membered heteroalkylene.
  • L 6 is independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L 6 is independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L 6 is independently substituted 2 to 3 membered heteroalkylene. In embodiments, L 6 is independently unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L 6 is independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L 6 is independently substituted 4 to 5 membered heteroalkylene. In embodiments, L 6 is independently unsubstituted 4 to 5 membered heteroalkylene.
  • L 6A is independently a bond or unsubstituted alkylene
  • L 6B is independently a bond, -NHC(O)-, or unsubstituted arylene
  • L 6C is independently a bond, unsubstituted alkylene, or unsubstituted arylene
  • L 6D is independently a bond or unsubstituted alkylene
  • L 6E is independently a bond or -NHC(O)-.
  • L 6A is independently a bond or unsubstituted alkylene.
  • L 6B is independently a bond, -NHC(O)-, or unsubstituted arylene.
  • L 6C is independently a bond, unsubstituted alkylene, or unsubstituted arylene.
  • L 6D is independently a bond or unsubstituted alkylene.
  • L 6E is independently a bond or -NHC(O)-.
  • L 6A is independently a bond or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • L 6A is independently unsubstituted C 1 -C 20 alkylene.
  • L 6A is independently unsubstituted C 1 -C 12 alkylene.
  • L 6A is independently unsubstituted C1-C8 alkylene. In embodiments, L 6A is independently unsubstituted C1-C6 alkylene. In embodiments, L 6A is independently unsubstituted C1-C4 alkylene. In embodiments, L 6A is independently unsubstituted ethylene. In embodiments, L 6A is independently unsubstituted methylene. In embodiments, L 6A is independently a bond. In embodiments, L 6B is independently a bond. In embodiments, L 6B is independently -NHC(O)-.
  • L 6B is independently unsubstituted arylene (e.g., C 6 -C 12 , C 6 -C 10 , or phenyl). In embodiments, L 6B is independently unsubstituted C 6 -C 12 arylene. In embodiments, L 6B is independently unsubstituted C6-C10 arylene. In embodiments, L 6B is independently unsubstituted phenylene. In embodiments, L 6B is independently unsubstituted naphthylene. In embodiments, L 6B is independently unsubstituted biphenylene.
  • arylene e.g., C 6 -C 12 , C 6 -C 10 , or phenyl
  • L 6B is independently unsubstituted C 6 -C 12 arylene.
  • L 6B is independently unsubstituted C6-C10 arylene.
  • L 6B is independently unsubstituted phenylene.
  • L 6B is independently
  • L 6C is independently a bond or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L 6C is independently unsubstituted C 1 -C 20 alkylene. In embodiments, L 6C is independently unsubstituted C 1 -C 12 alkylene. In embodiments, L 6C is independently unsubstituted C1-C8 alkylene. In embodiments, L 6C is independently unsubstituted C2-C8 alkynylene. In embodiments, L 6C is independently unsubstituted C 1 -C 6 alkylene.
  • alkylene e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2
  • L 6C is independently unsubstituted C 1 -C 4 alkylene. In embodiments, L 6C is independently unsubstituted ethylene. In embodiments, L 6C is independently unsubstituted methylene. In embodiments, L 6C is independently a bond or unsubstituted alkynylene (e.g., C2-C20, C2-C12, C2-C8, C2-C6, C2-C4, or C2-C2). In embodiments, L 6C is independently unsubstituted C 2 -C 20 alkynylene. In embodiments, L 6C is independently unsubstituted C2-C12 alkynylene.
  • alkynylene e.g., C2-C20, C2-C12, C2-C8, C2-C6, C2-C4, or C2-C2
  • L 6C is independently unsubstituted C2-C8 alkynylene. In embodiments, L 6C is independently unsubstituted C2-C6 alkynylene. In embodiments, L 6C is independently unsubstituted C 2 -C 4 alkynylene. In embodiments, L 6C is independently unsubstituted ethynylene. In embodiments, L 6C is independently unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L 6C is independently unsubstituted C 6 -C 12 arylene. In embodiments, L 6C is independently unsubstituted C 6 -C 10 arylene.
  • arylene e.g., C6-C12, C6-C10, or phenyl
  • L 6C is independently unsubstituted phenylene. In embodiments, L 6C is independently unsubstituted naphthylene. In embodiments, L 6C is independently a bond. In embodiments, L 6D is independently a bond or unsubstituted alkylene (e.g., C 1 -C 20 , C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L 6D is independently unsubstituted C1-C20 alkylene. In embodiments, L 6D is independently unsubstituted C1-C12 alkylene. In embodiments, L 6A is independently unsubstituted C 1 -C 8 alkylene.
  • L 6D is independently unsubstituted C1-C6 alkylene. In embodiments, L 6D is independently unsubstituted C1-C4 alkylene. In embodiments, L 6D is independently unsubstituted ethylene. In embodiments, L 6D is independently unsubstituted methylene. In embodiments, L 6D is independently a bond. In embodiments, L 6E is independently a bond. In embodiments, L 6E is independently -NHC(O)-. In embodiments, L 6A is independently a bond or unsubstituted C 1 -C 8 alkylene. In embodiments, L 6B is independently a bond, -NHC(O)-, or unsubstituted phenylene.
  • L 6C is independently a bond, unsubstituted C2-C8 alkynylene, or unsubstituted phenylene.
  • L 6D is independently a bond or unsubstituted C1-C8 alkylene.
  • L 6E is independently a bond or -NHC(O)-.
  • L 6 is independently a bond, , independently a bond.
  • L 6 is independently .
  • L 6 is independently .
  • L 6 is independently . embodiments, L 6 is independently . embodiments, L 6 is independently .
  • L 6 is independently .
  • L 6 is independently .
  • L 6 is independently .
  • L 5 is independently -NHC(O)-.
  • L 5 is independently -C(O)NH-.
  • L 5 is independently substituted or unsubstituted alkylene. In embodiments, L 5 is independently substituted or unsubstituted heteroalkylene. In embodiments, L 5 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L 5 is independently substituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • alkylene e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • L 5 is independently unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, L 5 is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L 5 is independently substituted C 1 -C 20 alkylene. In embodiments, L 5 is independently unsubstituted C 1 -C 20 alkylene. In embodiments, L 5 is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L 5 is independently substituted C1-C12 alkylene.
  • alkylene e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 .
  • L 5 is independently substituted or unsub
  • L 5 is independently unsubstituted C1-C12 alkylene. In embodiments, L 5 is independently substituted or unsubstituted C 1 -C 8 alkylene. In embodiments, L 5 is independently substituted C1-C8 alkylene. In embodiments, L 5 is independently unsubstituted C1-C8 alkylene. In embodiments, L 5 is independently substituted or unsubstituted C 1 -C 6 alkylene. In embodiments, L 5 is independently substituted C 1 -C 6 alkylene. In embodiments, L 5 is independently unsubstituted C 1 -C 6 alkylene. In embodiments, L 5 is independently substituted or unsubstituted C1-C4 alkylene.
  • L 5 is independently substituted C 1 -C 4 alkylene. In embodiments, L 5 is independently unsubstituted C 1 -C 4 alkylene. In embodiments, L 5 is independently substituted or unsubstituted ethylene. In embodiments, L 5 is independently substituted ethylene. In embodiments, L 5 is independently unsubstituted ethylene. In embodiments, L 5 is independently substituted or unsubstituted methylene. In embodiments, L 5 is independently substituted methylene. In embodiments, L 5 is independently unsubstituted methylene.
  • L 5 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • L 5 is independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • L 5 is independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L 5 is independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L 5 is independently substituted 2 to 20 membered heteroalkylene. In embodiments, L 5 is independently unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L 5 is independently substituted or unsubstituted 2 to 8 membered heteroalkylene.
  • L 5 is independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L 5 is independently substituted
  • L 5 is independently substituted 2 to 8 membered heteroalkylene. In embodiments, L 5 is independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 5 is independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 5 is independently substituted 2 to 6 membered heteroalkylene. In embodiments, L 5 is independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 5 is independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L 5 is independently substituted 4 to 6 membered heteroalkylene.
  • L 5 is independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L 5 is independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L 5 is independently substituted 2 to 3 membered heteroalkylene. In embodiments, L 5 is independently unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L 5 is independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L 5 is independently substituted 4 to 5 membered heteroalkylene. In embodiments, L 5 is independently unsubstituted 4 to 5 membered heteroalkylene.
  • L 5A is independently a bond or unsubstituted alkylene
  • L 5B is independently a bond, -NHC(O)-, or unsubstituted arylene
  • L 5C is independently a bond, unsubstituted alkylene, or unsubstituted arylene
  • L 5D is independently a bond or unsubstituted alkylene
  • L 5E is independently a bond or -NHC(O)-.
  • L 5A is independently a bond or unsubstituted alkylene.
  • L 5B is independently a bond, -NHC(O)-, or unsubstituted arylene.
  • L 5C is independently a bond, unsubstituted alkylene, or unsubstituted arylene.
  • L 5D is independently a bond or unsubstituted alkylene.
  • L 5E is independently a bond or -NHC(O)-.
  • L 5A is independently a bond or unsubstituted alkylene (e.g., C 1 -C 20 , C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • L 5A is independently unsubstituted C1-C20 alkylene.
  • L 5A is independently unsubstituted C1-C12 alkylene.
  • L 5A is independently unsubstituted C1-C8 alkylene. In embodiments, L 5A is independently unsubstituted C 1 -C 6 alkylene. In embodiments, L 5A is independently unsubstituted C1-C4 alkylene. In embodiments, L 5A is independently unsubstituted ethylene. In embodiments, L 5A is independently unsubstituted methylene. In embodiments, L 5A is independently a bond. In embodiments, L 5B is independently a bond. In embodiments, L 5B is independently -NHC(O)-.
  • L 5B is independently unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L 5B is independently unsubstituted C6-C12 arylene. In embodiments, L 5B is independently unsubstituted C 6 -C 10 arylene. In embodiments, L 5B is independently unsubstituted phenylene. In embodiments, L 5B is independently unsubstituted naphthylene.
  • arylene e.g., C6-C12, C6-C10, or phenyl
  • L 5C is independently a bond or unsubstituted alkylene (e.g., C 1 -C 20 , C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L 5C is independently unsubstituted C1-C20 alkylene. In embodiments, L 5C is independently unsubstituted C1-C12 alkylene. In embodiments, L 5C is independently unsubstituted C 1 -C 8 alkylene. In embodiments, L 5C is independently unsubstituted C 2 -C 8 alkynylene. In embodiments, L 5C is independently unsubstituted C1-C6 alkylene.
  • alkylene e.g., C 1 -C 20 , C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2
  • L 5C is independently unsubstituted C1-C20 alkylene. In embodiments
  • L 5C is independently unsubstituted C1-C4 alkylene. In embodiments, L 5C is independently unsubstituted ethylene. In embodiments, L 5C is independently unsubstituted methylene. In embodiments, L 5C is independently a bond or unsubstituted alkynylene (e.g., C2-C20, C2-C12, C2-C8, C2-C6, C2-C4, or C2-C2). In embodiments, L 5C is independently unsubstituted C2-C20 alkynylene. In embodiments, L 5C is independently unsubstituted C 2 -C 12 alkynylene.
  • alkynylene e.g., C2-C20, C2-C12, C2-C8, C2-C6, C2-C4, or C2-C2
  • L 5C is independently unsubstituted C2-C8 alkynylene. In embodiments, L 5C is independently unsubstituted C2-C6 alkynylene. In embodiments, L 5C is independently unsubstituted C2-C4 alkynylene. In embodiments, L 5C is independently unsubstituted ethynylene. In embodiments, L 5C is independently unsubstituted arylene (e.g., C 6 -C 12 , C 6 -C 10 , or phenyl). In embodiments, L 5C is independently unsubstituted C6-C12 arylene. In embodiments, L 5C is independently unsubstituted C6-C10 arylene.
  • arylene e.g., C 6 -C 12 , C 6 -C 10 , or phenyl
  • L 5C is independently unsubstituted phenylene. In embodiments, L 5C is independently unsubstituted naphthylene. In embodiments, L 5C is independently a bond. In embodiments, L 5D is independently a bond or unsubstituted alkylene (e.g., C1-C20, C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, L 5D is independently unsubstituted C1-C20 alkylene. In embodiments, L 5D is independently unsubstituted C1-C12 alkylene.
  • alkylene e.g., C1-C20, C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 .
  • L 5D is independently unsubstituted C1-C20 alkylene. In
  • L 5A is independently unsubstituted C1-C8 alkylene.
  • L 5D is independently unsubstituted C1-C6 alkylene.
  • L 5D is independently unsubstituted C 1 -C 4 alkylene.
  • L 5D is independently unsubstituted ethylene.
  • L 5D is independently unsubstituted methylene.
  • L 5D is independently a bond.
  • L 5E is independently a bond.
  • L 5E is independently -NHC(O)-.
  • L 5A is independently a bond or unsubstituted C1-C8 alkylene.
  • L 5B is independently a bond, -NHC(O)-, or unsubstituted phenylene.
  • L 5C is independently a bond, unsubstituted C 2 -C 8 alkynylene, or unsubstituted phenylene.
  • L 5D is independently a bond or unsubstituted C1-C8 alkylene.
  • L 5E is independently a bond or -NHC(O)-.
  • L 5 is independently a bond, , In e 5 mbodiments, L is independently a bond.
  • L 5 is independently .
  • L 5 is independently .
  • L 5 is independently .
  • L 5 is independently .
  • L 5 is independently In embodiments, L 5 is independently In embodiments, R 1 is independently In embodiments, R 1 is unsubstituted alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 1 is unsubstituted unbranched alkyl (e.g., C 1 -C 25 , C 1 -C 20 , C 1 -C 17 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • R 1 is unsubstituted alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • R 1 is unsubstituted un
  • R 1 is unsubstituted unbranched saturated alkyl (e.g., C 1 -C 25 , C 1 -C 20 , C 1 -C 17 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C1-C4, or C1-C2).
  • R 1 is unsubstituted unbranched unsaturated alkyl (e.g., C 1 -C 25 , C 1 -C 20 , C 1 -C 17 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • R 1 is unsubstituted C 1 -C 17 alkyl. In embodiments, R 1 is unsubstituted C11-C17 alkyl. In embodiments, R 1 is unsubstituted C13-C17 alkyl. In embodiments, R 1 is unsubstituted C 14 -C 15 alkyl. In embodiments, R 1 is unsubstituted C 15 alkyl. In embodiments, R 1 is unsubstituted C 14 alkyl. In embodiments, R 1 is unsubstituted unbranched C1-C17 alkyl. In embodiments, R 1 is unsubstituted unbranched C11-C17 alkyl.
  • R 1 is unsubstituted unbranched C 13 -C 17 alkyl. In embodiments, R 1 is unsubstituted unbranched C 14 -C 15 alkyl. In embodiments, R 1 is unsubstituted unbranched C14 alkyl. In embodiments, R 1 is unsubstituted unbranched C15 alkyl. In embodiments, R 1 is unsubstituted unbranched saturated C 1 -C 17 alkyl. In embodiments, R 1 is unsubstituted unbranched saturated C 11 -C 17 alkyl. In embodiments, R 1 is unsubstituted unbranched saturated C13-C17 alkyl.
  • R 1 is unsubstituted unbranched saturated C 14 -C 15 alkyl. In embodiments, R 1 is unsubstituted unbranched saturated C 14 alkyl. In embodiments, R 1 is unsubstituted unbranched saturated C 15 alkyl. In embodiments, R 1 is unsubstituted unbranched unsaturated C1-C17 alkyl. In embodiments, R 1 is unsubstituted unbranched unsaturated C11-C17 alkyl. In embodiments, R 1 is unsubstituted unbranched unsaturated C 13 -C 17 alkyl. In embodiments, R 1 is unsubstituted unbranched unsaturated C14-C15 alkyl.
  • R 1 is unsubstituted unbranched unsaturated C14 alkyl. In embodiments, R 1 is unsubstituted unbranched unsaturated C15 alkyl. In embodiments, R 2 is unsubstituted alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • R 2 is unsubstituted unbranched alkyl (e.g., C 1 -C 25 , C 1 -C 20 , C 1 -C 17 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • R 2 is unsubstituted unbranched saturated alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • R 2 is unsubstituted unbranched unsaturated alkyl (e.g., C 1 -C 25 , C 1 -C 20 , C 1 -C 17 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • R 2 is unsubstituted C1-C17 alkyl.
  • R 2 is unsubstituted C11-C17 alkyl.
  • R 2 is unsubstituted C13-C17 alkyl.
  • R 2 is unsubstituted C 14 -C 15 alkyl.
  • R 2 is unsubstituted C 14 alkyl. In embodiments, R 2 is unsubstituted C15 alkyl. In embodiments, R 2 is unsubstituted unbranched C1-C17 alkyl. In embodiments, R 2 is unsubstituted unbranched C 11 -C 17 alkyl. In embodiments, R 2 is unsubstituted unbranched C13-C17 alkyl. In embodiments, R 2 is unsubstituted unbranched C14-C15 alkyl. In embodiments, R 2 is unsubstituted unbranched C14 alkyl. In embodiments, R 2 is unsubstituted unbranched C 15 alkyl.
  • R 2 is unsubstituted unbranched saturated C 1 -C 17 alkyl. In embodiments, R 2 is unsubstituted unbranched saturated C11-C17 alkyl. In embodiments, R 2 is unsubstituted unbranched saturated C13-C17 alkyl. In embodiments, R 2 is unsubstituted unbranched saturated C 14 -C 15 alkyl. In embodiments, R 2 is unsubstituted unbranched saturated C14 alkyl. In embodiments, R 2 is unsubstituted unbranched saturated C15 alkyl. In embodiments, R 2 is unsubstituted unbranched unsaturated C1-C17 alkyl.
  • R 2 is unsubstituted unbranched unsaturated C 11 -C 17 alkyl. In embodiments, R 2 is unsubstituted unbranched unsaturated C13-C17 alkyl. In embodiments, R 2 is unsubstituted unbranched unsaturated C14-C15 alkyl. In embodiments, R 2 is unsubstituted unbranched unsaturated C 14 alkyl. In embodiments, R 2 is unsubstituted unbranched unsaturated C 15 alkyl. In embodiments, at least one of R 1 and R 2 is unsubstituted C 1 -C 19 alkyl.
  • At least one of R 1 and R 2 is unsubstituted C9-C19 alkyl. In embodiments, at least one of R 1 and R 2 is unsubstituted C11-C19 alkyl. In embodiments, at least one of R 1 and R 2 is unsubstituted C 13 -C 19 alkyl. In embodiments, R 1 is unsubstituted C1-C19 alkyl. In embodiments, R 1 is unsubstituted C9-C19 alkyl. In embodiments, R 1 is unsubstituted C11-C19 alkyl. In embodiments, R 1 is unsubstituted C 13 -C 19 alkyl.
  • R 1 is unsubstituted unbranched C1-C19 alkyl. In embodiments, R 1 is unsubstituted unbranched C9-C19 alkyl. In embodiments, R 1 is unsubstituted unbranched C11-C19 alkyl. In embodiments, R 1 is unsubstituted unbranched C13-C19 alkyl. In embodiments, R 1 is unsubstituted unbranched saturated C 1 -C 19 alkyl. In embodiments, R 1 is unsubstituted unbranched saturated C 9 -C 19 alkyl. In embodiments, R 1 is unsubstituted unbranched saturated C11-C19 alkyl.
  • R 1 is unsubstituted unbranched saturated C13-C19 alkyl. In embodiments, R 1 is unsubstituted unbranched unsaturated C 1 -C 19 alkyl. In embodiments, R 1 is unsubstituted unbranched unsaturated C 9 -C 19 alkyl. In embodiments, R 1 is unsubstituted unbranched unsaturated C11-C19 alkyl. In embodiments, R 1 is unsubstituted unbranched unsaturated C13-C19 alkyl. In embodiments, R 2 is unsubstituted C 1 -C 19 alkyl. In embodiments, R 2 is unsubstituted C9-C19 alkyl.
  • R 2 is unsubstituted C11-C19 alkyl. In embodiments, R 2 is unsubstituted C13-C19 alkyl. In embodiments, R 2 is unsubstituted unbranched C 1 -C 19 alkyl. In embodiments, R 2 is unsubstituted unbranched C 9 -C 19 alkyl. In embodiments, R 2 is unsubstituted unbranched C11-C19 alkyl. In embodiments, R 2 is unsubstituted unbranched C13-C19 alkyl. In embodiments, R 2 is unsubstituted unbranched saturated C 1 -C 19 alkyl.
  • R 2 is unsubstituted unbranched saturated C 9 -C 19 alkyl. In embodiments, R 2 is unsubstituted unbranched saturated C 11 -C 19 alkyl. In embodiments, R 2 is unsubstituted unbranched saturated C13-C19 alkyl. In embodiments, R 2 is unsubstituted unbranched unsaturated C1-C19 alkyl. In embodiments, R 2 is unsubstituted unbranched unsaturated C 9 -C 19 alkyl. In embodiments, R 2 is unsubstituted unbranched unsaturated C11-C19 alkyl.
  • R 2 is unsubstituted unbranched unsaturated C13-C19 alkyl.
  • L 3 is independently a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R 25 )-O-, -O-P(S)(R 25 )-O-, -O-P(O)(NR 23 R 24 )-N-, -O-P(S)(NR 23 R 24 )-N-, -O
  • L 3 is independently a bond, a -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO 2 -O-, -O-P(O)(S)-O-, -O-P(O)(R 25 )-O-, -O-P(S)(R 25 )-O-, -O-P(O)(NR 23 R 24 )-N-, -O-P(S)(NR 23 R 24 )-N-, -O-P(S)(NR 23 R 24 )-N-, -O-P(
  • L 3 is independently a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO 2 -O-, -O-P(O)(S)-O-, -O-P(O)(R 25 )-O-, -O-P(S)(R 25 )-O-, -O-P(O)(NR 23 R 24 )-N-, -O-P(S)(NR 23 R 24 )-N-, -O-P(O)(NR 23 R 24 )-N-, -O-P(O)
  • L 3 when L 3 is substituted, L 3 is substituted with a substituent group. In embodiments, when L 3 is substituted, L 3 is substituted with a size-limited substituent group. In embodiments, when L 3 is substituted, L 3 is substituted with a lower substituent group.
  • L 4 is independently a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R 25 )-O-, -O-P(S)(R 25 )-O-, -O-P(O)(NR 23 R 24 )-N-, -O-P(S)(NR 23 R 24 )-N-, -O-P(S)(NR 23 R 24 )-N-, -O-P(O)(NR
  • L 4 is a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R 25 )-O-, -O-P(S)(R 25 )-O-, -O-P(O)(NR 23 R 24 )-N-, -O-P(S)(NR 23 R 24 )-N-, -O-P(O)(NR 23 R 24 )-N-, -O-P(O)(NR 23
  • L 4 is a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R 25 )-O-, -O-P(S)(R 25 )-O-, -O-P(O)(NR 23 R 24 )-N-, -O-P(S)(NR 23 R 24 )-N-, -O-P(O)(NR 23 R 24 )-N-, -O-P(O)(NR 23
  • R 23 is independently hydrogen or unsubstituted alkyl (e.g., C1-C23, C1-C12, C1-C8, C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 23 is independently hydrogen. In embodiments, R 23 is independently unsubstituted C1-C23 alkyl.
  • R 23 is independently hydrogen or unsubstituted C1-C12 alkyl. In embodiments, R 23 is independently hydrogen or unsubstituted C 1 -C 10 alkyl. In embodiments, R 23 is independently hydrogen or unsubstituted C 1 -C 8 alkyl. In embodiments, R 23 is independently hydrogen or unsubstituted C 1 -C 6 alkyl. In embodiments, R 23 is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 23 is independently hydrogen or unsubstituted C1-C2 alkyl.
  • R 24 is independently hydrogen or unsubstituted alkyl (e.g., C 1 -C 23 , C 1 -C 12 , C 1 -C 8 , C1-C6, C1-C4, or C1-C2). In embodiments, R 24 is independently hydrogen. In embodiments, R 24 is independently unsubstituted C1-C23 alkyl. In embodiments, R 24 is independently hydrogen or unsubstituted C 1 -C 12 alkyl. In embodiments, R 24 is independently hydrogen or unsubstituted C1-C10 alkyl. In embodiments, R 24 is independently hydrogen or unsubstituted C1-C8 alkyl.
  • R 24 is independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R 24 is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 24 is independently hydrogen or unsubstituted C 1 -C 2 alkyl.
  • R 25 is independently hydrogen or unsubstituted alkyl (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 25 is independently hydrogen. In embodiments, R 25 is independently unsubstituted C 1 -C 23 alkyl. In embodiments, R 25 is independently hydrogen or unsubstituted C 1 -C 12 alkyl.
  • R 25 is independently hydrogen or unsubstituted C1-C10 alkyl. In embodiments, R 25 is independently hydrogen or unsubstituted C1-C8 alkyl. In embodiments, R 25 is independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R 25 is independently hydrogen or unsubstituted C 1 -C 4 alkyl. In embodiments, R 25 is independently hydrogen or unsubstituted C1-C2 alkyl.
  • L 5A is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 member
  • L 5A is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C 1 -C 20 , C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g.,
  • L 5A is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C 3 -C 10 , C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C
  • L 5A when L 5A is substituted, L 5A is substituted with a substituent group. In embodiments, when L 5A is substituted, L 5A is substituted with a size-limited substituent group. In embodiments, when L 5A is substituted, L 5A is substituted with a lower substituent group.
  • L 5B is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membere
  • L 5B is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to
  • L 5B is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, –C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted
  • L 5B when L 5B is substituted, L 5B is substituted with a substituent group. In embodiments, when L 5B is substituted, L 5B is substituted with a size-limited substituent group. In embodiments, when L 5B is substituted, L 5B is substituted with a lower substituent group.
  • L 5C is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 member
  • L 5C is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g.,
  • L 5C is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g.
  • L 5C when L 5C is substituted, L 5C is substituted with a substituent group. In embodiments, when L 5C is substituted, L 5C is substituted with a size-limited substituent group. In embodiments, when L 5C is substituted, L 5C is substituted with a lower substituent group.
  • L 5D is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membere
  • L 5D is a bond, -NH-, -O-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C 1 -C 20 , C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with
  • L 5D is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C 3 -C 10 , C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C
  • L 5D when L 5D is substituted, L 5D is substituted with a substituent group. In embodiments, when L 5D is substituted, L 5D is substituted with a size-limited substituent group. In embodiments, when L 5D is substituted, L 5D is substituted with a lower substituent group.
  • L 5E is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 member
  • L 5E is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to
  • L 5E is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted
  • L 5E when L 5E is substituted, L 5E is substituted with a substituent group. In embodiments, when L 5E is substituted, L 5E is substituted with a size-limited substituent group. In embodiments, when L 5E is substituted, L 5E is substituted with a lower substituent group.
  • L 6 is independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 member
  • L 6 is independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g.,
  • L 6 is independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C 1 -C 4 , or C 1 -C 2 ), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocyclo
  • L 6 when L 6 is substituted, L 6 is substituted with a substituent group. In embodiments, when L 6 is substituted, L 6 is substituted with a size-limited substituent group. In embodiments, when L 6 is substituted, L 6 is substituted with a lower substituent group.
  • L 6A is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 member
  • L 6A is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C 1 -C 20 , C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g.,
  • L 6A is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g.
  • L 6A when L 6A is substituted, L 6A is substituted with a substituent group. In embodiments, when L 6A is substituted, L 6A is substituted with a size-limited substituent group. In embodiments, when L 6A is substituted, L 6A is substituted with a lower substituent group.
  • L 6B is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membere
  • L 6B is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or
  • L 6B is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6)
  • L 6B when L 6B is substituted, L 6B is substituted with a substituent group. In embodiments, when L 6B is substituted, L 6B is substituted with a size-limited substituent group. In embodiments, when L 6B is substituted, L 6B is substituted with a lower substituent group.
  • L 6C is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 member
  • L 6C is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g.,
  • L 6C is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted
  • L 6C when L 6C is substituted, L 6C is substituted with a substituent group. In embodiments, when L 6C is substituted, L 6C is substituted with a size-limited substituent group. In embodiments, when L 6C is substituted, L 6C is substituted with a lower substituent group.
  • L 6D is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 member
  • L 6D is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C 1 -C 20 , C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g.,
  • L 6D is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C 3 -C 10 , C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ), unsubstit
  • L 6D when L 6D is substituted, L 6D is substituted with a substituent group. In embodiments, when L 6D is substituted, L 6D is substituted with a size-limited substituent group. In embodiments, when L 6D is substituted, L 6D is substituted with a lower substituent group.
  • L 6E is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membere
  • L 6E is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to
  • L 6E is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C 1 -C 20 , C 1 -C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (
  • L 6E when L 6E is substituted, L 6E is substituted with a substituent group. In embodiments, when L 6E is substituted, L 6E is substituted with a size-limited substituent group. In embodiments, when L 6E is substituted, L 6E is substituted with a lower substituent group. In embodiments, L 7 is independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • alkylene e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2
  • L 7 is independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).
  • L 7 is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C 1 -C 4 , or C 1 -C 2 ).
  • L 7 is independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • a substituent group e.g., a size-limited substituent group, or lower substituent group
  • unsubstituted heteroalkylene e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered.
  • L 7 is independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • L 7 is independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • L 7 is independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • a substituent group e.g., a size-limited substituent group, or lower substituent group
  • unsubstituted heteroalkenylene e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered.
  • L 7 is independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • L 7 is independently unsubstituted heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).
  • L 7 when L 7 is substituted, L 7 is substituted with a substituent group.
  • R 1 is unsubstituted alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 1 is unsubstituted C1-C25 alkyl. In embodiments, R 1 is unsubstituted C 1 -C 20 alkyl. In embodiments, R 1 is unsubstituted C 1 -C 12 alkyl.
  • R 1 is unsubstituted C 1 -C 8 alkyl. In embodiments, R 1 is unsubstituted C 1 -C 6 alkyl. In embodiments, R 1 is unsubstituted C1-C4 alkyl. In embodiments, R 1 is unsubstituted C1-C2 alkyl. In embodiments, R 1 is unsubstituted branched alkyl (e.g., C 1 -C 25 , C 1 -C 20 , C 1 -C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 1 is unsubstituted branched C1-C25 alkyl.
  • R 1 is unsubstituted branched C1-C20 alkyl. In embodiments, R 1 is unsubstituted branched C 1 -C 12 alkyl. In embodiments, R 1 is unsubstituted branched C 1 -C 8 alkyl. In embodiments, R 1 is unsubstituted branched C1-C6 alkyl. In embodiments, R 1 is unsubstituted branched C1-C4 alkyl. In embodiments, R 1 is unsubstituted branched C1-C2 alkyl.
  • R 1 is unsubstituted unbranched alkyl (e.g., C 1 -C 25 , C 1 -C 20 , C 1 -C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 1 is unsubstituted unbranched C1-C25 alkyl. In embodiments, R 1 is unsubstituted unbranched C1-C20 alkyl. In embodiments, R 1 is unsubstituted unbranched C 1 -C 12 alkyl. In embodiments, R 1 is unsubstituted unbranched C1-C8 alkyl.
  • R 1 is unsubstituted unbranched alkyl (e.g., C 1 -C 25 , C 1 -C 20 , C 1 -C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 1 is unsubstituted unbranched C1-
  • R 1 is unsubstituted unbranched C1-C6 alkyl. In embodiments, R 1 is unsubstituted unbranched C1-C4 alkyl. In embodiments, R 1 is unsubstituted unbranched C 1 -C 2 alkyl. In embodiments, R 1 is unsubstituted branched saturated alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 1 is unsubstituted branched saturated C 1 -C 25 alkyl.
  • R 1 is unsubstituted branched saturated C 1 -C 20 alkyl. In embodiments, R 1 is unsubstituted branched saturated C 1 -C 12 alkyl. In embodiments, R 1 is unsubstituted branched saturated C1-C8 alkyl. In embodiments, R 1 is unsubstituted branched saturated C1-C6 alkyl. In embodiments, R 1 is unsubstituted branched saturated C1-C4 alkyl. In embodiments, R 1 is unsubstituted branched saturated C 1 -C 2 alkyl.
  • R 1 is unsubstituted branched unsaturated alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 1 is unsubstituted branched unsaturated C 1 -C 25 alkyl. In embodiments, R 1 is unsubstituted branched unsaturated C 1 -C 20 alkyl. In embodiments, R 1 is unsubstituted branched unsaturated C1-C12 alkyl. In embodiments, R 1 is unsubstituted branched unsaturated C1-C8 alkyl.
  • R 1 is unsubstituted branched unsaturated C1-C6 alkyl. In embodiments, R 1 is unsubstituted branched unsaturated C 1 -C 4 alkyl. In embodiments, R 1 is unsubstituted branched saturated C1-C2 alkyl. In embodiments, R 1 is unsubstituted unbranched saturated alkyl (e.g., C1-C25, C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 1 is unsubstituted unbranched saturated C 1 -C 25 alkyl.
  • R 1 is unsubstituted unbranched saturated C1-C20 alkyl. In embodiments, R 1 is unsubstituted unbranched saturated C1-C12 alkyl. In embodiments, R 1 is unsubstituted unbranched saturated C1-C8 alkyl. In embodiments, R 1 is unsubstituted unbranched saturated C 1 -C 6 alkyl. In embodiments, R 1 is unsubstituted unbranched saturated C1-C4 alkyl. In embodiments, R 1 is unsubstituted unbranched saturated C1-C2 alkyl.
  • R 1 is unsubstituted unbranched unsaturated alkyl (e.g., C 1 -C 25 , C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 1 is unsubstituted unbranched unsaturated C1-C25 alkyl. In embodiments, R 1 is unsubstituted unbranched unsaturated C 1 -C 20 alkyl. In embodiments, R 1 is unsubstituted unbranched unsaturated C 1 -C 12 alkyl. In embodiments, R 1 is unsubstituted unbranched unsaturated C 1 -C 8 alkyl.
  • R 1 is unsubstituted unbranched unsaturated alkyl (e.g., C 1 -C 25 , C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 1 is
  • R 1 is unsubstituted unbranched unsaturated C1-C6 alkyl. In embodiments, R 1 is unsubstituted unbranched unsaturated C1-C4 alkyl. In embodiments, R 1 is unsubstituted unbranched unsaturated C 1 -C 2 alkyl. In embodiments, R 1 is unsubstituted C9-C19 alkyl. In embodiments, R 1 is unsubstituted branched C9-C19 alkyl. In embodiments, R 1 is unsubstituted unbranched C9-C19 alkyl. In embodiments, R 1 is unsubstituted branched saturated C 9 -C 19 alkyl.
  • R 1 is unsubstituted branched unsaturated C9-C19 alkyl. In embodiments, R 1 is unsubstituted unbranched saturated C9-C19 alkyl. In embodiments, R 1 is unsubstituted unbranched unsaturated C 9 -C 19 alkyl. In embodiments, R 2 is unsubstituted alkyl (e.g., C 1 -C 25 , C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C1-C6, C1-C4, or C1-C2). In embodiments, R 2 is unsubstituted C1-C25 alkyl.
  • R 2 is unsubstituted C1-C20 alkyl. In embodiments, R 2 is unsubstituted C1-C12 alkyl. In embodiments, R 2 is unsubstituted C 1 -C 8 alkyl. In embodiments, R 2 is unsubstituted C 1 -C 6 alkyl. In embodiments, R 2 is unsubstituted C1-C4 alkyl. In embodiments, R 2 is unsubstituted C1-C2 alkyl.
  • R 2 is unsubstituted branched alkyl (e.g., C 1 -C 25 , C 1 -C 20 , C 1 -C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 2 is unsubstituted branched C1-C25 alkyl. In embodiments, R 2 is unsubstituted branched C1-C20 alkyl. In embodiments, R 2 is unsubstituted branched C1-C12 alkyl. In embodiments, R 2 is unsubstituted branched C1-C8 alkyl.
  • R 2 is unsubstituted branched C 1 -C 6 alkyl. In embodiments, R 2 is unsubstituted branched C1-C4 alkyl. In embodiments, R 2 is unsubstituted branched C1-C2 alkyl. In embodiments, R 2 is unsubstituted unbranched alkyl (e.g., C 1 -C 25 , C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). In embodiments, R 2 is unsubstituted unbranched C 1 -C 25 alkyl.
  • R 2 is unsubstituted unbranched C1-C20 alkyl. In embodiments, R 2 is unsubstituted unbranched C1-C12 alkyl. In embodiments, R 2 is unsubstituted unbranched C 1 -C 8 alkyl. In embodiments, R 2 is unsubstituted unbranched C 1 -C 6 alkyl. In embodiments, R 2 is unsubstituted unbranched C1-C4 alkyl. In embodiments, R 2 is unsubstituted unbranched C1-C2 alkyl.
  • R 2 is unsubstituted branched saturated alkyl (e.g., C 1 -C 25 , C 1 -C 20 , C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 2 is unsubstituted branched saturated C1-C25 alkyl. In embodiments, R 2 is unsubstituted branched saturated C1-C20 alkyl. In embodiments, R 2 is unsubstituted branched saturated C 1 -C 12 alkyl. In embodiments, R 2 is unsubstituted branched saturated C 1 -C 8 alkyl.
  • R 2 is unsubstituted branched saturated C1-C6 alkyl. In embodiments, R 2 is unsubstituted branched saturated C1-C4 alkyl. In embodiments, R 2 is unsubstituted branched saturated C1-C2 alkyl. In embodiments, R 2 is unsubstituted branched unsaturated alkyl (e.g., C 1 -C 25 , C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 2 is unsubstituted branched unsaturated C1-C25 alkyl.
  • R 2 is unsubstituted branched unsaturated C1-C20 alkyl. In embodiments, R 2 is unsubstituted branched unsaturated C 1 -C 12 alkyl. In embodiments, R 2 is unsubstituted branched unsaturated C1-C8 alkyl. In embodiments, R 2 is unsubstituted branched unsaturated C1-C6 alkyl. In embodiments, R 2 is unsubstituted branched unsaturated C 1 -C 4 alkyl. In embodiments, R 2 is unsubstituted branched saturated C 1 -C 2 alkyl.
  • R 2 is unsubstituted unbranched saturated alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 2 is unsubstituted unbranched saturated C 1 -C 25 alkyl. In embodiments, R 2 is unsubstituted unbranched saturated C1-C20 alkyl. In embodiments, R 2 is unsubstituted unbranched saturated C1-C12 alkyl. In embodiments, R 2 is unsubstituted unbranched saturated C1-C8 alkyl.
  • R 2 is unsubstituted unbranched saturated C 1 -C 6 alkyl. In embodiments, R 2 is unsubstituted unbranched saturated C1-C4 alkyl. In embodiments, R 2 is unsubstituted unbranched saturated C1-C2 alkyl. In embodiments, R 2 is unsubstituted unbranched unsaturated alkyl (e.g., C 1 -C 25 , C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 2 is unsubstituted unbranched unsaturated C1-C25 alkyl.
  • R 2 is unsubstituted unbranched unsaturated C 1 -C 20 alkyl. In embodiments, R 2 is unsubstituted unbranched unsaturated C 1 -C 12 alkyl. In embodiments, R 2 is unsubstituted unbranched unsaturated C 1 -C 8 alkyl. In embodiments, R 2 is unsubstituted unbranched unsaturated C1-C6 alkyl. In embodiments, R 2 is unsubstituted unbranched unsaturated C1-C4 alkyl. In embodiments, R 2 is unsubstituted unbranched unsaturated C 1 -C 2 alkyl.
  • R 2 is unsubstituted C9-C19 alkyl. In embodiments, R 2 is unsubstituted branched C9-C19 alkyl. In embodiments, R 2 is unsubstituted unbranched C9-C19 alkyl. In embodiments, R 2 is unsubstituted branched saturated C 9 -C 19 alkyl. In embodiments, R 2 is unsubstituted branched unsaturated C9-C19 alkyl. In embodiments, R 2 is unsubstituted unbranched saturated C9-C19 alkyl. In embodiments, R 2 is unsubstituted unbranched unsaturated C 9 -C 19 alkyl.
  • R 3 is hydrogen, -NH 2 , -OH, -SH, -C(O)H, -C(O)NH 2 , -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, -N3, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered,
  • R 3 is hydrogen, -NH 2 , -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, -N3, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted
  • R 3 is hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C (O)OH, -OC(O)H, –N 3 , unsubstituted alkyl (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), unsubstituted heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C10, C3-C8, C3-C6, C4-C6,
  • the uptake motif is represented by the structure: The uptake motif is attached to the remainder of the compunds provided here through the –L3-L4- moiety as set forth in Formula (I) above. The wavy line represents attachment to the L 4 linker in Formula (I).
  • the compound comprises one or more uptake motifs having a structure shown in Table 3 below.
  • the compound comprises a DTx-01-01 motif in Table 3.
  • the compound comprises a DTx-01-03 motif 1 of Table 3.
  • the compound comprises a DTx-01-06 motif in Table 3.
  • the compound comprises a DTx-01-08 motif in Table 3.
  • the compound comprises a DTx-01-11 motif in Table 3.
  • the compound comprises a DTx-01-13 motif in Table 3.
  • the compound comprises a DTx-01-30 motif in Table 3. In embodiments, the compound comprises a DTx-01-31 motif in Table 3. In embodiments, the compound comprises a DTx-01-32 motif in Table 3. In embodiments, the compound comprises a DTx-01-33 motif in Table 3. In embodiments, the compound comprises a DTx-01-34 motif in Table 3. In embodiments, the compound comprises a DTx-01-35 motif in Table 3. In embodiments, the compound comprises a DTx-01-36 motif in Table 3. In embodiments, the compound comprises a DTx-01-39 motif in Table 3. In embodiments, the compound comprises a DTx-01-43 motif in Table 3. In embodiments, the compound comprises a DTx-01-44 motif in Table 3.
  • the compound comprises a DTx-01-45 motif in Table 3. In embodiments, the compound comprises a DTx-01-46 motif in Table 3. In embodiments, the compound comprises a DTx-01-50 motif in Table 3. In embodiments, the compound comprises a DTx-01-51 motif in Table 3. In embodiments, the compound comprises a DTx-01-52 motif in Table 3. In embodiments, the compound comprises a DTx-01-53 motif in Table 3. In embodiments, the compound comprises a DTx-01-54 motif in Table 3. In embodiments, the compound comprises a DTx-01-55 motif in Table 3. In embodiments, the compound comprises a DTx-03-06 motif in Table 3. In embodiments, the compound comprises a DTx-03-50 motif in Table 3.
  • the compound comprises a DTx-03-51 motif in Table 3. In embodiments, the compound comprises a DTx-03-52 motif in Table 3. In embodiments, the compound comprises a DTx-03-53 motif in Table 3. In embodiments, the compound comprises a DTx-03-54 motif in Table 3. In embodiments, the compound comprises a DTx-03-55 motif in Table 3. In embodiments, the compound comprises a DTx-04-01 motif in Table 3. In embodiments, the compound comprises a DTx-05-01 motif in Table 3. In embodiments, the compound comprises a DTx-06-06 motif in Table 3. In embodiments, the compound comprises a DTx-06-50 motif in Table 3.
  • the compound comprises a DTx-06-51 motif in Table 3. In embodiments, the compound comprises a DTx-06-52 motif in Table 3. In embodiments, the compound comprises a DTx-06-53 motif in Table 3. In embodiments, the compound comprises a DTx-06-54 motif in Table 3. In embodiments, the compound comprises a DTx-06-55 motif in Table 3. In embodiments, the compound comprises a DTx-08-01 motif in Table 3. In embodiments, the compound comprises a DTx-09-01 motif in Table 3. In embodiments, the compound comprises a DTx-10-01 motif in Table 3. In embodiments, the compound comprises a DTx-11-01 motif in Table 3. In embodiments, the compound comprises a DTx-01-60 motif in Table 3.
  • the compound comprises a DTx-01-61 motif in Table 3. In embodiments, the compound comprises a DTx-01-62 motif in Table 3. In embodiments, the compound comprises a DTx-01-63 motif in Table 3. In embodiments, the compound comprises a DTx-01-64 motif in Table 3. In embodiments, the compound comprises a DTx-01-65 motif in Table 3. In embodiments, the compound comprises a DTx-01-66 motif in Table 3. In embodiments, the compound comprises a DTx-01-67 motif in Table 3. In embodiments, the compound comprises a DTx-01-68 motif in Table 3. In embodiments, the compound comprises a DTx-01-69 motif in Table 3. In embodiments, the compound comprises a DTx-01-70 motif in Table 3.
  • the compound comprises a DTx-01-71 motif in Table 3. In embodiments, the compound comprises a DTx-01-72 motif in Table 3. In embodiments, the compound comprises a DTx-01-73 motif in Table 3. In embodiments, the compound comprises a DTx-01-74 motif in Table 3. In embodiments, the compound comprises a DTx-01-75 motif in Table 3. In embodiments, the compound comprises a DTx-01-76 motif in Table 3. In embodiments, the compound comprises a DTx-01-77 motif in Table 3. In embodiments, the compound comprises a DTx-01-78 motif in Table 3. In embodiments, the compound comprises a DTx-01-79 motif in Table 3. In embodiments, the compound comprises a DTx-01-80 motif in Table 3.
  • the compound comprises a DTx-01-81 motif in Table 3. In embodiments, the compound comprises a DTx-01-82 motif in Table 3. In embodiments, the compound comprises a DTx-01-83 motif in Table 3. In embodiments, the compound comprises a DTx-01-84 motif in Table 3. In embodiments, the compound comprises a DTx-01-85 motif in Table 3. In embodiments, the compound comprises a DTx-01-86 motif in Table 3. In embodiments, the compound comprises a DTx-01-87 motif in Table 3. In embodiments, the compound comprises a DTx-01-88 motif in Table 3. In embodiments, the compound comprises a DTx-01-89 motif in Table 3. In embodiments, the compound comprises a DTx-01-90 motif in Table 3.
  • the compound comprises a DTx-01-91 motif in Table 3. In embodiments, the compound comprises a DTx-01-92 motif in Table 3. In embodiments, the compound comprises a DTx-01-93 motif in Table 3. In embodiments, the compound comprises a DTx-01-94 motif in Table 3. In embodiments, the compound comprises a DTx-01-95 motif in Table 3. In embodiments, the compound comprises a DTx-01-96 motif in Table 3. In embodiments, the compound comprises a DTx-01-97 motif in Table 3. In embodiments, the compound comprises a DTx-01-98 motif in Table 3. In embodiments, the compound comprises a DTx-01-99 motif in Table 3. In embodiments, the compound comprises a DTx-01-100 motif in Table 3. In embodiments, the compound comprises a DTx-01-101 motif in Table 3. Table 3: Uptake Motif
  • DTx-01-01 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein , DTx-01-03 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-06 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-08 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-11 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-13 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-30 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-31 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-32 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-33 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-34 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-35 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-36 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-39 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-43 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-44 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-45 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-46 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-50 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-51 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-52 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-53 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-54 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-55 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-03-06 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-03-50 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-03-51 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-03-52 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-03-53 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-03-54 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-03-55 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-04-01 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-05-01 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-06-06 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-06-50 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-06-51 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-06-52 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-06-53 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-06-54 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-06-55 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-08-01 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-09-01 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-10-01 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-11-01 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-60 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-61 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-62 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-63 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-64 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-65 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-66 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-67 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-68 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-69 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-70 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-71 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-72 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-73 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-74 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-75 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-76 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-77 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-78 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-79 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-80 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-81 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-82 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-83 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-84 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-85 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-86 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-87 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-88 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-89 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-90 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-91 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-92 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-93 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-94 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-95 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-96 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-97 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-98 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-99 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-100 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-101 is attached to the double-stranded nucleic acid (A) through -L 3 - L 4 -, wherein .
  • DTx-01-01 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein DTx-01-03 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 - .
  • DTx-01-06 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-08 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-11 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-13 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-30 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-31 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-32 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-33 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-34 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-35 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-36 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-39 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-43 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-44 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-45 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-46 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-50 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-51 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-52 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-53 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-54 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-55 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-03-06 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-03-50 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-03-51 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-03-52 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-03-53 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-03-54 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-03-55 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-04-01 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-05-01 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-06-06 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-06-50 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-06-51 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein .
  • DTx-06-52 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein .
  • DTx-06-53 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-06-54 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein .
  • DTx-06-55 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - i
  • DTx-08-01 is attached to the double-stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-09-01 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-10-01 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-11-01 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-60 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-61 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-62 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-63 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-64 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-65 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-66 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-67 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-68 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-69 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-70 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-71 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-72 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-73 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-74 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-75 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-76 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-77 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-78 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-79 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-80 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-81 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-82 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-83 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-84 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-85 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-86 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-87 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-88 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-89 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-90 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-91 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-92 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-93 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-94 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-95 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-96 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-97 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-98 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-99 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-100 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is .
  • DTx-01-101 is attached to the double- stranded nucleic acid (A) through -L 3 -L 4 -, wherein -L 3 -L 4 - is In embodiments, -L 3 -L 4 - i the phosphate group is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L 6 is , L 5 is -NHC(O)-, R 3 is hydrogen, R 1 is unsubstituted unbranched C15 alkyl, and R 2 is unsubstituted unbranched C 15 alkyl.
  • the phosphate group of -L 3 -L 4 - is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand
  • L 6 is
  • L 5 is -NHC(O)-
  • R 3 is hydrogen
  • R 1 is unsubstituted unbranched C13 alkyl
  • R 2 is unsubstituted unbranched C13 alkyl.
  • -L 3 is attached to a phosphate group at the 3’ carbon of the 3’ terminal nucleotide of the sense strand
  • L 6 is
  • L 5 is -NHC(O)-
  • R 3 is hydrogen
  • R 1 is unsubstituted unbranched C15 alkyl
  • R 2 is unsubstituted unbranched C15 alkyl.
  • -L 3 is attached to a phosphate group at the the 3’ carbon of the 3’ terminal nucleotide of the sense strand
  • L 6 is
  • L 5 is -NHC(O)-
  • R 3 is hydrogen
  • R 1 is unsubstituted unbranched C 13 alkyl
  • R 2 is unsubstituted unbranched C 13 alkyl.
  • a compound is selected from DT-000429, DT-000430, DT-000431, DT-000432, DT-000735, DT-000736, DT-000737, DT-000738, DT-000776, DT-000777, DT-000778, DT-000785, DT-000786, DT-000787, DT-000828, DT-000829, DT-000830, DT-000831, and DT-000832.
  • a compound is DT-000429.
  • the compound is DT-000430.
  • a compound is DT-000431.
  • a compound is DT-000432.
  • a compound is DT-000735. In embodiments, a compound is DT-000736. In embodiments, a compound is DT-000737. In embodiments, a compound is DT-000738. In embodiments, a compound is DT-000776. In embodiments, a compound is DT-000777. In embodiments, a compound is DT-000778. In embodiments, a compound is DT-000785. In embodiments, a compound is DT-000786. In embodiments, a compound is DT-000787. In embodiments, a compound is DT-000828. In embodiments, a compound is DT-000829. In embodiments, a compound is DT-000830.
  • a compound is DT-000831. In embodiments, a compound is DT-000832. In embodiments, a compound is DT-001373. In embodiments, a compound is DT-001374. In embodiments, a compound is DT-001375. In embodiments, a compound is DT-001386.
  • Table S The structures of DT-000429, DT-000430, DT-000431, and DT-000432 are shown in Table S.
  • a compound is DT-000430, where -L 3 -L 4 - is , the phosphate group of -L 3 -L 4 - is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L 6 is , L 5 is -NHC(O)-, R 3 is hydrogen, R 1 is unsubstituted unbranched C13 alkyl, R 2 is unsubstituted unbranched C13 alkyl, the nucleotide sequence of the sense strand is 5’- G F S G M S A F A M U F A M U F G M U F C M A F A M U F G M A F C M U F -3’ (SEQ ID NO: 265), and the nucleotide sequence of the antisense strand is 5’- AM S AF S AMGFUMCFAMUFUMGFAMCFAMUFAMUFUMCFCM S T S T-3’ (SEQ ID NO: 37), where a nucle
  • a compound is DT-000432, where -L 3 -L 4 - is , the phosphate group of -L 3 -L 4 - is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L 6 is , L 5 is -NHC(O)-, R 3 is hydrogen, R 1 is unsubstituted unbranched C13 alkyl, R 2 is unsubstituted unbranched C13 alkyl, the nucleotide sequence of the sense strand is 5’- U F S G M S A F C M U F U M U F G M A F C M U F U M G F A M U F G M A F S A M S G F -3’ (SEQ ID NO: 267), and the nucleotide sequence of the antisense strand is 5’- CM S UF S UMCFAMUFCMAFAMGFUMCFAMAFAMGFUMCFAM S T S T-3’ (SEQ ID NO: 57), where
  • a compound is DT-000776, where -L 3 -L 4 - is , the phosphate group of -L 3 -L 4 - is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L 6 is , L 5 is -NHC(O)-, R 3 is hydrogen, R 1 is unsubstituted unbranched C13 alkyl, R 2 is unsubstituted unbranched C13 alkyl, the nucleotide sequence of the sense strand is 5’- A F S U M S G F G M A F A M U F A M U F G M U F C M A F A M U F G M A F C M U F -3’ (SEQ ID NO: 222), and the nucleotide sequence of the antisense strand is 5’- AM S AF S AMGFUMCFAMUFUMGFAMCFAMUFAMUFUMCFCMAFUM S GM S GM-3’ (SEQ ID NO: 222), and the nucleo
  • a compound is DT-001373, where -L 3 -L 4 - is , the phosphate group of -L 3 -L 4 - is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L 6 is L 5 is -NHC(O)-, 3 s hydrogen, R 1 R i is unsubstituted unbranched C 13 alkyl, R 2 is unsubstituted unbranched C 13 alkyl, the nucleotide sequence of the sense strand is 5’- CF S UM S UFUMGFAMCFUMUFGMAFUMGFAMAFGMUFUMUF S GM S AF-3’ (SEQ ID NO: 242), and the nucleotide sequence of the antisense strand is 5’- U M S C F S A M A F A M C F U M U F C M A F U M C F A M A F G M U F C M A F A M A F G M S C M A F A M A F G M S
  • a compound is DT-001374, where -L 3 -L 4 - is the phosphate group of -L 3 -L 4 - is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L 6 is , is -NHC(O)-, R 3 is hydrogen, R 1 is unsubstituted unbranched C 13 alkyl, R 2 is unsubstituted unbranched C 13 alkyl, the nucleotide sequence of the sense strand is 5’- UF S GM S AFCMUFUMGFAMUFGMAFAMGFUMUFUMGFAMGF S GM S UF-3’ (SEQ ID NO: 243), and the nucleotide sequence of the antisense strand is 5’- A M S C F S C M U F C M A F A M A F C M U F C F A M U F C M A F A M G F U M C F A M S A M -3’ (SEQ ID NO:
  • a compound is DT-001375, where -L 3 -L 4 - is , the phosphate group of -L 3 -L 4 - is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L 6 is , L 5 is -NHC(O)-, R 3 is hydrogen, R 1 is unsubstituted unbranched C 13 alkyl, R 2 is unsubstituted unbranched C 13 alkyl, the nucleotide sequence of the sense strand is 5’- C F S U M S U F G M A F U M G F A M A F G M U F U M U F G M A F G M G F U M A F S A M S A F -3’ (SEQ ID NO: 244), and the nucleotide sequence of the antisense strand is 5’- UM S UF S UMAFCMCFUMCFAMAFAMCFUMUFCMAFUMCFAMAFGM S UM S CM-3’ (SEQ ID NO:
  • a compound is DT-001386, where -L 3 -L 4 - is , the phosphate group of -L 3 -L 4 - is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L 6 is , L 5 is -NHC(O)-, R 3 is hydrogen, R 1 is unsubstituted unbranched C13 alkyl, R 2 is unsubstituted unbranched C13 alkyl, the nucleotide sequence of the sense strand is 5’- A M S U M S G F G M A F A M U F A M U F G M U F C M A F A M U F G M A F C M U F S U M S U F -3’ (SEQ ID NO: 245), and the nucleotide sequence of the antisense strand is 5’- AM S AF S AMGFUMCFAMUFUMGFAMCFAMUFAMUFUMCFCMAFUM S GM S GM-3’ (SEQ ID NO: 245)
  • a ligand is a saturated or unsaturated C8-C20 alkyl. In embodiments, a ligand contains a saturated or unsaturated C6-C18 alkyl.
  • Pharmaceutical Salts and Compositions The compounds provided herein may be present as a pharmaceutical salt. In embodiments, the pharmaceutical salt is a sodium salt.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • a non-bridging heteroatom e.g., an S ⁇ or O ⁇
  • a linkage of a compound provided herein may be protonated or associated with a counterion such as Na + , K + , etc.
  • An acceptable salt (e.g. a pharmaceutically acceptable salt) of a compound may comprise fewer cationic counterions (such as Na + , K + , etc.) than there are non-bridging heteroatoms per molecule (i.e., some non-bridging heteroatoms are protonated and some are associated with counterions).
  • a phosphate linkage attaching an -L 3 -L 4 - to a carbon of a nucleotide includes a non-bridging heteroatom.
  • a phosphodiester linkage of a nucleic acid includes a non-bridging heteroatom.
  • a phosphorothioate linkage of a nucleic acid includes a non-bridging heteroatom.
  • the compounds provided herein may be present as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable diluent.
  • the compound is present in a pharmaceutically acceptable diluent.
  • the pharmaceutically acceptable diluent is a sterile aqueous solution.
  • the sterile aqueous solution is a sterile saline solution.
  • a pharmaceutical composition may be prepared so that it is compatible with the intended mode of administration of the compound. Routes of administration of compounds include intravenous, intradermal, subcutaneous, transdermal, intramuscular, topical, and ocular administration. Pharmaceutical compositions may be prepared for ocular administration to the eye in the form of an injection. Pharmaceutical compositions suitable for injection include sterile aqueous solutions, including sterile saline solutions. Pharmaceutical compositions suitable for injection may also be a lyophilized compound that is subsequently reconstitute with a pharmaceutically acceptable diluent in preparation for injection.
  • compositions may be prepared for ocular administration to the eye in the form of an ophthalmic suspension (i.e. eye drops).
  • Additional pharmaceutical preparations suitable for ocular administration include emulsions, ointments, aqueous gels, nanomicelles, nanoparticles, liposomes, dendrimers, implants, contact lenses, nanosuspensions, microneedles, and in situ thermosensitive gels.
  • Methods of Use The compounds provided herein inhibit the expression of the neural retina leucine zipper (NRL) mRNA.
  • NNL neural retina leucine zipper
  • a method for inhibiting the expression of neural retina leucine zipper (NRL) mRNA in a cell comprising contacting a cell with a nucleic compound provided herein, thereby inhibiting the expression of neural retina leucine zipper (NRL) in the cell.
  • the cell is a photoreceptor cell.
  • the cell is in vivo.
  • the cell is in vitro.
  • a method for inhibiting the expression of neural retina leucine zipper (NRL) in a subject comprising administering to the subject an effective amount of a compound provided herein, thereby inhibiting the expression of neural retina leucine zipper (NRL) in the subject.
  • retinitis pigmentosa is provided herein.
  • a method for treating retinitis pigmentosa in a subject in need thereof comprising administering to the subject an effective amount compound provided herein.
  • a method for delaying the onset of retinitis pigmentosa in a subject in need thereof comprising administering to the subject a compound provided herein.
  • Retinitis pigmentosa may be diagnosed by a medical professional using one or more available examination procedures which are routine tests of vision and retinal function. Nyctalopia, or impaired vision at night or in low lighting, is an indicator of retinitis pigmentosa.
  • subjects with retinitis pigmentosa may exhibit visual field constriction, which is an absolute or relative decrease in retinal sensitivity and may be determined by mapping the visual field of each eye of the subject to assess the subject’s scope of vision (central and peripheral vision). Further, subjects with retinitis pigmentosa may exhibit decreased visual acuity, which is often determined by the ability of the subject to identify letters or numbers on a standardized eye chart from a specific viewing distance. Morphological abnormalities in the retina may be found in subject with retinitis pigmentosa and may be detected by optical coherence tomography (OCT), which is a method of examining the retinal structure in situ.
  • OCT optical coherence tomography
  • Subjects with retinitis pigmentosa may exhibit a reduced electrical responses of various cell types in the retina, including photoreceptor cells, to a light stimulus.
  • the electrical activity generated in retinal cells in response to a light stimulus may be measured by an electroretinogram (ERG).
  • ERG electroretinogram
  • an examination of the retina in subjects may identify abnormal retinal pigmentation, or dark pigment deposits in the retina of the subject.
  • the subject prior to administration of the compound to the subject, the subject has been diagnosed as having retinitis pigmentosa.
  • a subject is diagnosed as having retinitis pigmentosa based on one or more indicators of the disease: a family history of retinitis pigmentosa; decreased visual acuity; abnormal retinal morphology; the presence of nyctalopia; visual field constriction; a reduced response to light stimulus; and retinal pigmentation abnormalities.
  • the administration of the compound to the subject improves one or more indicators of retinitis pigmentosa in the subject.
  • administration of the compound to the subject slows the progression of one or more indicators of retinitis pigmentosa in the subject.
  • an indicator is visual acuity.
  • an indicator is retinal morphology.
  • an indicator is nyctalopia. In embodiments, an indicator is visual field constriction. In embodiments, an indicator is response to a light stimulus. In embodiments, a response to a light stimulus is measured by a electroretinogram. In embodiments, an indicator is retinal pigmentation.
  • Compounds provided herein may be administered via ocular administration. In embodiments, ocular administration is intraocular administration. Intraocular administration is achieved by injection into a specific area of the eye. In embodiments, intraocular administration is subconjunctival administration. In embodiments, intraocular administration is intravitreal administration. In embodiments, intraocular administration is retrobulbar administration. In embodiments, intraocular administration is intracameral administration.
  • ocular administration is topical administration.
  • topical administration comprises administration of an ophthalmic suspension.
  • topical administration comprises administration of an ointment.
  • at least one additional therapy is administered to the subject.
  • the at least one additional therapy is vitamin A.
  • compounds provided herein are for use in therapy.
  • pharmaceutical compositions provided herein are for use in therapy.
  • the therapy is the treatment of retinitis pigmentosa.
  • Formulations are available to facilitate compound use both in vitro and as therapeutic agents. Accordingly, in embodiments, a compound provided herein is present in a formulation. Compounds may be formulated with cationic lipids to facilitate transfection into cells.
  • Suitable cationic lipid reagents for transfection include Lipofectamine reagents, such as Lipofectamine RNAiMAX.
  • nucleic acids compounds may be encapsulated into lipid nanoparticles.
  • Lipid nanoparticles generally comprise a cationic lipid, a non-cationic lipid, and a lipid that prevents aggregation of the nanoparticle.
  • Suitable cationic lipids include DLin-MC3-DMA ((6Z,9Z,28Z,31Z)-Heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate), DLin-KC2-DMA (2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane) and the lipidoid C12-200.
  • Suitable non-cationic lipids include, for example, DOPC (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine) and DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine).
  • lipids that prevent aggregation include, for example, polyethylene glycol (PEG)-lipids, such as PEG-C-DMA (3-N-[( ⁇ -methoxypoly(ethylene glycol)2000)carbamoyl]-1,2-dimyristyloxy-propylamine), PEG2000-C-DMG ( ⁇ -(3- ⁇ [1,2-di(myristyloxy)proponoxy]carbonylamino ⁇ propyl)- ⁇ -methoxy, polyoxyethylene), and mPEG-DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]).
  • PEG polyethylene glycol
  • PEG-C-DMA 3-N-[( ⁇ -methoxypoly(ethylene glycol)2000)carbamoyl]-1,2-dimyristyloxy-propylamine
  • PEG2000-C-DMG ⁇ -(
  • a compound comprising an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein each of the antisense strand and sense strands is 15 to 25 nucleotides in length, the nucleotide sequence of the antisense strand is at least 90% complementary to the nucleotide sequence of the NRL mRNA (SEQ ID NO: 1), and the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand.
  • SEQ ID NO: 1 the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand.
  • each of the antisense strand and sense strands is 15 to 25 nucleotides in length
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 contiguous nucleotides of any one of nucleotides 501 to 563 of SEQ ID NO: 1, nucleotides 602 to 626 of SEQ ID NO: 1, nucleotides 623 to 654 of SEQ ID NO: 1, nucleotides 684 to 710 of SEQ ID NO: 1, nucleotides 741 to 765 of SEQ ID NO: 1, nucleotides 759 to 777 of SEQ ID NO: 1, nucleotides 882 to 909 of SEQ ID NO: 1, or nucleotides 1111 to 1133 of SEQ ID NO: 1, and the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand.
  • Embodiment P3 The compound of Embodiment P1 or P2, wherein the antisense strand is 17 to 23 nucleotides in length.
  • Embodiment P4. The compound of any one of Embodiments P1 to P3, wherein the antisense strand is 19 to 21 nucleotides in length.
  • Embodiment P5. The compound of any one of Embodiments P1 to P3, wherein the antisense strand is 21 to 23 nucleotides in length.
  • Embodiment P6 The compound of any one of Embodiments P1 to P5, wherein the antisense strand is 19 nucleotides in length.
  • Embodiment P8. The compound of any one of Embodiments P1 to P5, wherein the antisense strand is 21 nucleotides in length.
  • Embodiment P9. The compound of any one of Embodiments P1 to P5, wherein the antisense strand is 22 nucleotides in length.
  • Embodiment P10. The compound of any one of Embodiments P1 to P5, wherein the antisense strand is 23 nucleotides in length.
  • Embodiment P11 The compound of any one of Embodiments P1 to P10, wherein the sense strand is 17 to 23 nucleotides in length.
  • Embodiment P12 The compound of any one of Embodiments P1 to P10, wherein the sense strand is 19 to 21 nucleotides in length.
  • Embodiment P13 The compound of any one of Embodiments P1 to P10, wherein the sense strand is 21 to 23 nucleotides in length.
  • Embodiment P14 The compound of any one of Embodiments P1 to P13, wherein the sense strand is 19 nucleotides in length.
  • Embodiment P15 The compound of any one of Embodiments P1 to P13, wherein the sense strand is 20 nucleotides in length.
  • Embodiment P16 The compound of any one of Embodiments P1 to P10, wherein the sense strand is 19 to 21 nucleotides in length.
  • Embodiment P14 The compound of any one of Embodiments P13, wherein the sense strand is 19 nucleotides in length.
  • Embodiment P15 The compound of any one
  • Embodiment P17 The compound of any one of Embodiments P1 to P13 wherein the sense strand is 22 nucleotides in length.
  • Embodiment P18 The compound of any one of Embodiments P1 to P13, wherein the sense strand is 23 nucleotides in length.
  • Embodiment P19 The compound of any one of Embodiments P1 to P18, wherein the double-stranded region is 15 to 25 nucleotide pairs in length.
  • Embodiment P20 The compound of any one of Embodiments P1 to P13, wherein the sense strand is 21 nucleotides in length.
  • Embodiment P17 The compound of any one of Embodiments P1 to P13 wherein the sense strand is 22 nucleotides in length.
  • Embodiment P18 The compound of any one of Embodiments P1 to P13, wherein the sense strand is 23 nucleotides in length.
  • Embodiment P19 The compound of any
  • Embodiment P21 The compound of any one of Embodiments P1 to P18, wherein the double-stranded region is 19 to 21 nucleotide pairs in length.
  • Embodiment P22 The compound of any one of Embodiments P1 to P18, wherein the double-stranded region is 19 nucleotide pairs in length.
  • Embodiment P23 The compound of any one of Embodiments P1 to P18, wherein the double-stranded region is 20 nucleotide pairs in length.
  • Embodiment P24 The compound of any one of Embodiments P1 to P18, wherein the double-stranded region is 17 to 23 nucleotide pairs in length.
  • Embodiment P27 The compound of any one of Embodiments P1 to P18, wherein the double-stranded region is 21 nucleotide pairs in length.
  • Embodiment P25 The compound of any one of Embodiments P1 to P24, wherein the nucleotide sequence of the sense strand has no more than one mismatch to the nucleotide sequence of the antisense strand.
  • Embodiment P26 The compound of any one of Embodiments P1 to P24, wherein the nucleotide sequence of the sense strand has no mismatches to the nucleotide sequence of the antisense strand.
  • Embodiment P27 The compound of any one of Embodiments P1 to P18, wherein the double-stranded region is 21 nucleotide pairs in length.
  • Embodiment P25 The compound of any one of Embodiments P1 to P24, wherein the nucleotide sequence of the sense strand has no more than one mismatch to the
  • nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1.
  • nucleotide sequence of the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75.
  • SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75 Embodiment P29.
  • nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75.
  • SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75 Embodiment P30.
  • Embodiment P28 wherein the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75.
  • Embodiment P31 Embodiment P31.
  • the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75, and wherein the nucleotide sequence of the antisense strand is 100% complementary to 23 contiguous nucleotides of SEQ ID NO: 1.
  • nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74.
  • SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74 Embodiment P33.
  • Embodiment P34 The compound of any one of Embodiments P27 to P31, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74.
  • Embodiment P35 The compound of any one of Embodiments P27 to P31, wherein the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74.
  • SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74 Embodiment P35.
  • the sense strand is 21 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74, and wherein the nucleotide sequence of the sense strand is identical to 21 contiguous nucleotides of SEQ ID NO: 1.
  • Embodiment P36 Embodiment P36.
  • Embodiment P3 to P26 wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1.
  • Embodiment P37 The compound of Embodiment P36, wherein the nucleotide sequence of the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 93, 95, and 97.
  • Embodiment P38 Embodiment P38.
  • the compound of Embodiment P37 wherein the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 93, 95, and 97.
  • Embodiment P39 The compound of Embodiment P37, wherein the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 93, 95, and 97.
  • Embodiment P40 Embodiment P40.
  • Embodiment P37 wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96, and wherein the nucleotide sequence of the antisense strand is 100% complementary 23 contiguous nucleotides of SEQ ID NO: 1.
  • Embodiment P41 The compound of any one of Embodiments P36 to P40, wherein the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96.
  • Embodiment P42 Embodiment P42.
  • Embodiment P44 The compound of any one of Embodiments P36 to P40, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96.
  • Embodiment P43 The compound of any one of Embodiments P36 to P40, wherein the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96.
  • Embodiment P44 Embodiment P44.
  • Embodiment P45 The compound of any one of Embodiments P36 to P40, wherein the sense strand is 21 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96, and wherein the nucleotide sequence of the sense strand is identical to 21 contiguous nucleotides of SEQ ID NO: 1.
  • Embodiment P45 Embodiment P45.
  • nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1.
  • nucleotide sequence of the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109.
  • Embodiment P47 The compound of Embodiment P46, wherein the nucleotide sequence of antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109.
  • Embodiment P48 The compound of Embodiment P46, wherein the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109.
  • Embodiment P49 Embodiment P49.
  • Embodiment P46 wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109, and wherein the nucleotide sequence of the antisense strand is 100% complementary 23 contiguous nucleotides of SEQ ID NO: 1.
  • Embodiment P50 The compound of any one of Embodiments P45 to P49, wherein the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 8, 10, 2, 4, 104, 106, and 108.
  • Embodiment P51 Embodiment P51.
  • Embodiment P45 to P49 wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 8, 10, 2, 4, 104, 106, and 108.
  • Embodiment P52 The compound of any one of Embodiments P45 to P49, wherein the sense strand is 19 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 8, 10, 2, 4, 104, 106, and 108.
  • Embodiment P53 Embodiment P53.
  • the sense strand is 21 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 8, 10, 2, 4, 104, 106, and 108, and wherein the nucleotide sequence of the sense strand is identical to a 21 contiguous nucleotides of SEQ ID NO: 1.
  • Embodiment P54 is identical to a 21 contiguous nucleotides of SEQ ID NO: 1.
  • Embodiment P3 to P26 wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1.
  • Embodiment P55 The compound of Embodiment P54, wherein the nucleotide sequence of the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119.
  • Embodiment P56 is
  • the compound of Embodiment P55 wherein the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119.
  • Embodiment P57 The compound of Embodiment P55, wherein the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119.
  • Embodiment P58 Embodiment P58.
  • Embodiment P55 wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119, and wherein the nucleotide sequence of the antisense strand is 100% complementary 23 contiguous nucleotides of SEQ ID NO: 1.
  • Embodiment P59 The compound of any one of Embodiments P54 to P58, wherein the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 114, 116, and 118.
  • Embodiment P60 Embodiment P60.
  • Embodiment P62 The compound of any one of Embodiments P54 to P58, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 114, 116, and 118.
  • Embodiment P61 The compound of any one of Embodiments P54 to P58, wherein the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 114, 116, and 118.
  • Embodiment P62 Embodiment P62.
  • Embodiment P63 Embodiment P63.
  • the compound of Embodiment P62 wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1.
  • Embodiment P64 The compound of Embodiment P63, wherein the nucleotide sequence of the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20 or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133.
  • Embodiment P65 Embodiment P65.
  • Embodiment P64 wherein the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133.
  • Embodiment P66 The compound of Embodiment P64, wherein the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133.
  • Embodiment P67 Embodiment P67.
  • Embodiment P64 wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133, and wherein the nucleotide sequence of the antisense strand is 100% complementary to 23 contiguous nucleotides of SEQ ID NO: 1.
  • Embodiment P68 The compound of any one of Embodiments P63 to P67, wherein the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 128, 130, and 132.
  • Embodiment P69 Embodiment P69.
  • Embodiment P71 The compound of any one of Embodiments P63 to P67, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 128, 130, and 132.
  • Embodiment P70 The compound of any one of Embodiments P63 to P67, wherein the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 128, 130, and 132.
  • Embodiment P71 Embodiment P71.
  • Embodiment P72. The compound of any one of Embodiments P3 to P26, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, or 19 contiguous nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1.
  • Embodiment P73 Embodiment P73.
  • the compound of Embodiment P72, wherein the nucleotide sequence of the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or 21 contiguous nucleotides of SEQ ID NO: 141.
  • Embodiment P74. The compound of Embodiment P73, wherein the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of SEQ ID NO: 141.
  • Embodiment P75 The compound of Embodiment P73, wherein antisense strand is 21 nucleotides in length and comprises a nucleotide sequence that is identical to the nucleotide sequence of SEQ ID NO: 141.
  • Embodiment P73 wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of the nucleotide sequence of SEQ ID NO: 141, and wherein the nucleotide sequence of the antisense strand is 100% complementary to 23 contiguous nucleotides of SEQ ID NO: 1.
  • Embodiment P77 The compound of any one of Embodiments P72 to P76, wherein the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of SEQ ID NO: 140.
  • Embodiment P78 Embodiment P78.
  • Embodiment P72 to P76 wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to the nucleotide sequence of SEQ ID NO: 140.
  • Embodiment P79. The compound of any one of Embodiments P72 to P76, wherein the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to the nucleotide sequence of SEQ ID NO: 140.
  • Embodiment P80 Embodiment P80.
  • Embodiment P81 The compound of any one of Embodiments P72 to P76, wherein the sense strand is 21 nucleotides in length and nucleotides 1 to 19 of the nucleotide sequence of SEQ ID NO: 140, and wherein the nucleotide sequence of the sense strand is identical to 21 contiguous nucleotides of SEQ ID NO: 1.
  • Embodiment P81 The compound of any one of Embodiments P72 to P76, wherein the sense strand is 21 nucleotides in length and nucleotides 1 to 19 of the nucleotide sequence of SEQ ID NO: 140, and wherein the nucleotide sequence of the sense strand is identical to 21 contiguous nucleotides of SEQ ID NO: 1.
  • nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1.
  • the compound of Embodiment P81, wherein the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20 or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19.
  • Embodiment P83 Embodiment P83.
  • the compound of Embodiment P82 wherein the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19.
  • Embodiment P84 The compound of Embodiment P82, wherein the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19.
  • Embodiment P85 Embodiment P85.
  • Embodiment P82 wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19, and wherein the nucleotide sequence of the antisense strand is 100% complementary to 23 contiguous nucleotides of SEQ ID NO: 1.
  • Embodiment P86 The compound of any one of Embodiments P81 to P85, wherein the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID: 170, 172, 22, 12, 14, 16, and 18.
  • Embodiment P87 Embodiment P87.
  • Embodiment P89 Embodiment P89.
  • the sense strand is 21 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID: 170, 172, 22, 12, 14, 16, and 18, and wherein the nucleotide sequence of the sense strand is identical to 21 contiguous nucleotides of SEQ ID NO: 1.
  • Embodiment P90 is a nucleotide sequence selected from SEQ ID: 170, 172, 22, 12, 14, 16, and 18, and wherein the nucleotide sequence of the sense strand is identical to 21 contiguous nucleotides of SEQ ID NO: 1.
  • Embodiment P92 The compound of any one of Embodiments P3 to P26, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or 23 contiguous nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1.
  • Embodiment P91 The compound of Embodiment P90, wherein the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20 or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 193 and 195.
  • Embodiment P92 Embodiment P92.
  • Embodiment P91 wherein the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 193 and 195.
  • Embodiment P93 The compound of Embodiment P91, wherein the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 193 and 195.
  • Embodiment P94 Embodiment P94.
  • Embodiment P91 wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 193 and 195, and wherein the nucleotide sequence of the antisense strand is 100% complementary to 23 contiguous nucleotides of SEQ ID NO: 1.
  • Embodiment P95 The compound of any one of Embodiments P90 to P94, wherein the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 192 and 194.
  • Embodiment P96 Embodiment P96.
  • Embodiment P98 The compound of any one of Embodiments P90 to P94, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 192 and 194.
  • Embodiment P97 The compound of any one of Embodiments P90 to P94, wherein the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 192 and 194.
  • Embodiment P98 Embodiment P98.
  • Embodiment P99. The compound of any one of Embodiments P1 to P97, wherein the nucleotide sequence of the antisense strand is at least 95% complementary to SEQ ID NO: 1.
  • Embodiment P100 Embodiment P100.
  • Embodiment P101 The compound of any one of Embodiments P1 to P100, wherein the antisense strand and the sense strand are not covalently linked.
  • Embodiment P102 The compound of any one of Embodiments P1 to P99, wherein the hybridization of the antisense strand to the sense strand forms at least one blunt end.
  • Embodiment P103 The compound of Embodiment P102, wherein the hybridization of the antisense strand to the sense strand forms a blunt end at each terminus of the compound.
  • Embodiment P104 The compound of any one of Embodiments P1 to P99, wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1.
  • Embodiment P105 The compound of Embodiment P104, wherein the sense strand comprises the 3’ nucleotide overhang.
  • Embodiment P106 The compound of Embodiment P104, wherein the antisense strand comprises the 3’ nucleotide overhang.
  • Embodiment P107 The compound of Embodiment P104, wherein each of the sense strand and the antisense strand comprises a 3’ nucleotide overhang of one to five nucleotides.
  • Embodiment P108 The compound of any one of Embodiments P1 to P102, wherein at least one strand comprises a 3’ nucleotide overhang of one to five nucleotides.
  • each nucleotide of the 3’ nucleotide overhang of the antisense strand is complementary to SEQ ID NO: 1.
  • Embodiment P109. The compound of Embodiment P106 or Embodiment P107, wherein each nucleotide of the 3’ nucleotide overhang of the antisense strand is not complementary to SEQ ID NO: 1 Embodiment P110.
  • the compound of any one of Embodiments P104 to P109, wherein each nucleotide of the 3’ nucleotide overhang is a deoxythymidine.
  • Embodiment P104 to P110 The compound of any one of Embodiments P104 to P110, wherein the 3’ nucleotide overhang is two nucleotides in length.
  • Embodiment P112. The compound of any one of Embodiments P1 to P111, wherein at least one nucleotide of the antisense strand is a modified nucleotide.
  • Embodiment P113. The compound of any one of Embodiments P1 to P112, wherein at least one nucleotide of the sense strand is a modified nucleotide.
  • Embodiment P114 The compound of any one of Embodiments P104 to P110, wherein the 3’ nucleotide overhang is two nucleotides in length.
  • Embodiment P112. The compound of any one of Embodiments P111, wherein at least one nucleotide of the antisense strand is a modified nucleotide.
  • Embodiment P113. The
  • each nucleotide of the antisense strand forming the double-stranded region is a modified nucleotide.
  • Embodiment P115 The compound of any one of Embodiments P1 to P114, wherein each nucleotide of the sense strand forming the double-stranded region is a modified nucleotide.
  • Embodiment P116 The compound of any one of Embodiments P112 to P115, wherein the modified nucleotide comprises one or more of a modified sugar moiety, a modified internucleotide linkage, and a 5’-terminal modified phosphate group.
  • Embodiment P117 The compound of any one of Embodiments P112 to P115, wherein the modified nucleotide comprises one or more of a modified sugar moiety, a modified internucleotide linkage, and a 5’-terminal modified phosphate group.
  • the compound of Embodiment P116, wherein the modified nucleotide comprising a modified sugar moiety is selected from a 2’-fluoro nucleotide, a 2’- O-methyl nucleotide, a 2’-O-methoxyethyl nucleotide, and a bicyclic sugar nucleotide.
  • Embodiment P118. The compound of Embodiment P116, wherein the modified internucleotide linkage is a phosphorothioate internucleotide linkage.
  • Embodiment P118 wherein the first two internucleotide linkages at the 5’ terminus of the sense strand and the last two internucleotide linkages at the 3’ terminus of the sense strand are phosphorothioate internucleotide linkages.
  • Embodiment P120 The compound of Embodiment P119, wherein the first two internucleotide linkages at the 5’ terminus of the antisense strand and the last two internucleotide linkages at the 3’ terminus of the antisense strand are phosphorothioate internucleotide linkages.
  • Embodiment P121 wherein the first two internucleotide linkages at the 5’ terminus of the antisense strand and the last two internucleotide linkages at the 3’ terminus of the antisense strand are phosphorothioate internucleotide linkages.
  • Embodiment P117 wherein the covalent linkage of the bicyclic sugar is selected from a 4’-CH(CH3)-O-2’ linkage, a 4'-(CH2)2-O-2' linkage, a 4'-CH(CH 2 -OMe)-O-2' linkage, 4’-CH 2 -N(CH 3 )-O-2’ linkage, and 4’-CH 2 -N(H)- O-2’ linkage.
  • Embodiment P122 The compound of Embodiment P117, wherein the 5’-terminal modified phosphate group is a 5’-(E)-vinylphosphonate.
  • Embodiment P123 wherein the 5’-terminal modified phosphate group is a 5’-(E)-vinylphosphonate.
  • nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O- methylnucleotides
  • nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-flouronucleotides
  • nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides
  • the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages
  • each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P124 The compound of any one of Embodiments P1 to P122, wherein the antisense strand is 19 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O- methylnucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-flouronucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P125 The compound of Embodiment P123 or Embodiment P124, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’- fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides, and nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P126 The compound of Embodiment P123 or Embodiment P124, wherein the sense strand is 19 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoro nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P127 The compound of any one of Embodiments P1 to P122, wherein the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methylnucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’- flouronucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P128 The compound of Embodiment P127, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P129 The compound of Embodiment P127, wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta- D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage Embodiment P130.
  • nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methylnucleotides and nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’- flouronucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P131 The compound of Embodiment P130, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P132 The compound of Embodiment P130, wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta-D- deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P133 The compound of any one of Embodiments P1 to P122, wherein the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methylnucleotides and nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’- flouronucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P134 The compound of Embodiment P133, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-O-methyl nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P135. The compound of Embodiment P133, wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta-D- deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P136 The compound of any one of Embodiments P1 to P135, wherein the compound comprises a ligand covalently linked to the double-stranded nucleic acid.
  • Embodiment P137 The compound of Embodiment P136, wherein the compound has the structure: wherein A is the double-stranded nucleic acid; wherein t is an integer from 1 to 5; L 3 and L 4 are independently a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO2-O-, -O-P(O)(S)-
  • Embodiment P138 The compound of Embodiment P137, wherein t is 1. Embodiment P139. The compound of Embodiment P137, wherein t is 2. Embodiment P140. The compound of Embodiment P137, wherein t is 3. Embodiment P141. The compound of any one of Embodiments P137 to P140, wherein A is the sense strand. Embodiment P142. The compound of any one of Embodiments P137 to P141, wherein A is the antisense strand. Embodiment P143. The compound of one of Embodiments P137 to P142, wherein each of R 23 , R 24 and R 25 is independently hydrogen or unsubstituted C 1 -C 3 alkyl.
  • Embodiment P144 The compound of one of Embodiments P137 to P143, wherein one L 3 is attached to a 3’ carbon of a nucleotide.
  • Embodiment P145 The compound of Embodiment P144, wherein the 3’ carbon is the 3’ carbon of a 3’ terminal nucleotide.
  • Embodiment P146 The compound of one of Embodiments P137 to P141, wherein one L 3 is attached to a 5’ carbon of a nucleotide.
  • Embodiment P147 The compound of Embodiment P146, wherein the 5’ carbon is the 5’ carbon of a 5’ terminal nucleotide.
  • Embodiment P148 The compound of one of Embodiments P146, wherein the 5’ carbon is the 5’ carbon of a 5’ terminal nucleotide.
  • Embodiment P149 The compound of one of Embodiments P137 to P141, wherein one L 3 is attached to a 2’ carbon of a nucleotide.
  • Embodiment P149. The compound of one of Embodiments P137 to P148, wherein L 3 and L 4 are independently a bond, -NH-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -OPO2-O-, -O- P(O)(S)-O-, -O-P(O)(CH3)-O-, -O-P(S)(CH3)-O-, -O-P(O)(N(CH3)2)-N-, -O-P(O)(N(CH3)2)- O-, -O-P(S)(N(CH 3 ) 2 )-N-, -O-P(S)(N(CH 3 ) 2 )-O-, - P(O)
  • Embodiment P150 The compound of one of Embodiments P137 to P149, wherein L 3 is independently .
  • Embodiment P151. The compound of one of Embodiments P137 to P149, wherein L 3 is independently -OPO2-O- or –OP(O)(S)-O-.
  • Embodiment P152. The compound of one of Embodiments P137 to P149, wherein L 3 is independently –O-.
  • Embodiment P153 The compound of any one of Embodiments P137 to P149, wherein L 3 is independently -C(O)-.
  • Embodiment P157 The compound of any one of Embodiments P137 to P149, wherein L 3 is independently -O-P(O)(N(CH 3 ) 2 )-N-.
  • Embodiment P155 The compound of one of Embodiments P137 to P152, wherein L 4 is independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.
  • Embodiment P156 The compound of one of Embodiments P137 to P155, wherein L 4 is independently –L 7 -NH-C(O)- or –L 7 -C(O)-NH-, wherein L 7 is substituted or unsubstituted alkylene.
  • Embodiment P157 The compound of any one of Embodiments P137 to P149, wherein L 3 is independently -O-P(O)(N(CH 3 ) 2 )-N-.
  • Embodiment P155 The compound of one of Embodiments P137 to P
  • Embodiment P158 The compound of one of Embodiments P137 to P156, wherein L 4 is independently .
  • Embodiment P159. The compound of one of Embodiments P137 to P158, wherein –L 3 -L 4 - is independently –O-L 7 -NH-C(O)- or –O-L 7 -C(O)-NH-, wherein L 7 is independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene.
  • Embodiment P160 is independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene.
  • Embodiment P159 wherein –L 3 -L 4 - is independently –O-L 7 -NH-C(O)-, wherein L 7 is independently substituted or unsubstituted C 5 - C 8 alkylene.
  • Embodiment P161. The compound of Embodiment P160, wherein –L 3 -L 4 - is .
  • Embodiment P162 wherein –L 3 -L 4 - is independently -OPO2-O-L 7 -NH-C(O)- or –OP(O)(S)-O-L 7 -NH-C(O)-, wherein L 7 is independently substituted or unsubstituted C 5 -C 8 alkylene.
  • Embodiment P164 The compound of Embodiment P163, wherein –L 3 -L 4 - is Embodiment P165.
  • the compound of Embodiment P164, wherein an –L 3 -L 4 - is carbon of a 3’ terminal nucleotide.
  • Embodiment P166 is independently -OPO2-O-L 7 -NH-C(O)- or –OP(O)(S)-O-L 7 -NH-C(O)-, wherein L 7 is independently substituted or unsubstituted C 5 -C 8 alkylene.
  • Embodiment P164 The compound
  • Embodiment P164 wherein an –L 3 -L 4 - is attached to the 5’ carbon of a 5’ terminal nucleotide.
  • Embodiment P167 The compound of Embodiment P164, wherein an –L 3 -L 4 - is independently and is attached to a 2’ carbon.
  • Embodiment P168 The compound of one of Embodiments P127 to P167, wherein R 3 is independently hydrogen.
  • Embodiment P169 The compound of one of Embodiments P127 to P168, wherein L 6 is independently -NHC(O)-, –C(O)NH-,substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • Embodiment P170 The compound of Embodiment P169, wherein L 6 is independently -NHC(O)-.
  • Embodiment P171. The compound of Embodiment P169, wherein L 6A is independently a bond or unsubstituted alkylene; L 6B is independently a bond, -NHC(O)-, or unsubstituted arylene; L 6C is independently a bond, unsubstituted alkylene, or unsubstituted arylene; L 6D is independently a bond or unsubstituted alkylene; and L 6E is independently a bond or -NHC(O)-.
  • Embodiment P169 wherein L 6A is independently a bond or unsubstituted C1-C8 alkylene; L 6B is independently a bond, -NHC(O)-, or unsubstituted phenylene; L 6C is independently a bond, unsubstituted C 2 -C 8 alkynylene, or unsubstituted phenylene; L 6D is independently a bond or unsubstituted C 1 -C 8 alkylene; and L 6E is independently a bond or -NHC(O)-.
  • Embodiment P173. The compound of one of Embodiments P127 to P168, wherein Embodiment P174.
  • Embodiment P173 The compound of one of Embodiments P127 to P173, wherein L 5 is independently -NHC(O)-, –C(O)NH-,substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • Embodiment P175. The compound of one of Embodiments P127 to P173, wherein L 5 is independently -NHC(O)-.
  • Embodiment P176 Embodiment P176.
  • L 5A is independently a bond or unsubstituted alkylene
  • L 5B is independently a bond, -NHC(O)-, or unsubstituted arylene
  • L 5C is independently a bond, unsubstituted alkylene, or unsubstituted arylene
  • L 5D is independently a bond or unsubstituted alkylene
  • L 5E is independently a bond or -NHC(O)-.
  • Embodiments P127 to P173 wherein L 5A is independently a bond or unsubstituted C 1 -C 8 alkylene; L 5B is independently a bond, -NHC(O)-, or unsubstituted phenylene; L 5C is independently a bond, unsubstituted C2-C8 alkynylene, or unsubstituted phenylene; L 5D is independently a bond or unsubstituted C 1 -C 8 alkylene; and L 5E is independently a bond or -NHC(O)-.
  • Embodiment P178 The compound of one of Embodiments P127 to P173, wherein Embodiment P179.
  • Embodiment P187 The compound of one of Embodiments P127 to P173, wherein R 1 is unsubstituted unbranched C1-C17 alkyl.
  • Embodiment P184 The compound of one of Embodiments P127 to P173, wherein R 1 is unsubstituted unbranched C 11 -C 17 alkyl.
  • Embodiment P185 The compound of one of Embodiments P127 to P173, wherein R 1 is unsubstituted unbranched C13-C17 alkyl.
  • Embodiment P186 The compound of one of Embodiments P127 to P173, wherein R 1 is unsubstituted unbranched C 14 -C 15 alkyl.
  • Embodiment P187 The compound of one of Embodiments P127 to P173, wherein R 1 is unsubstituted unbranched C 14 -C 15 alkyl.
  • Embodiment P188 The compound of one of Embodiments P127 to P173, wherein R 1 is unsubstituted unbranched saturated C1-C17 alkyl.
  • Embodiment P189 The compound of one of Embodiments P127 to P173, wherein R 1 is unsubstituted unbranched saturated C 13 -C 17 alkyl.
  • Embodiment P190 The compound of one of Embodiments P127 to P173, wherein R 1 is unsubstituted unbranched saturated C14-C15 alkyl.
  • Embodiment P192 The compound of one of Embodiments P127 to P190, wherein R 2 is unsubstituted C11-C17 alkyl.
  • Embodiment P193 The compound of one of Embodiments P127 to P190, wherein R 2 is unsubstituted C13-C17 alkyl.
  • Embodiment P194. The compound of one of Embodiments P127 to P190, wherein R 2 is unsubstituted C 14 -C 15 alkyl.
  • Embodiment P195 The compound of one of Embodiments P127 to P190, wherein R 2 is unsubstituted C 14 -C 15 alkyl.
  • Embodiment P199 The compound of one of Embodiments P127 to P190, wherein R 2 is unsubstituted unbranched C1-C17 alkyl.
  • Embodiment P196 The compound of one of Embodiments P127 to P190, wherein R 2 is unsubstituted unbranched C 11 -C 17 alkyl.
  • Embodiment P197 The compound of one of Embodiments P127 to P190, wherein R 2 is unsubstituted unbranched C13-C17 alkyl.
  • Embodiment P198 The compound of one of Embodiments P127 to P190, wherein R 2 is unsubstituted unbranched C14-C15 alkyl.
  • Embodiment P199 The compound of one of Embodiments P127 to P190, wherein R 2 is unsubstituted unbranched C14-C15 alkyl.
  • Embodiment P200 The compound of one of Embodiments P127 to P190, wherein R 2 is unsubstituted unbranched saturated C1-C17 alkyl.
  • Embodiment P200 The compound of one of Embodiments P127 to P190, wherein R 2 is unsubstituted unbranched saturated C11-C17 alkyl.
  • Embodiment P201 The compound of one of Embodiments P127 to P190, wherein R 2 is unsubstituted unbranched saturated C 13 -C 17 alkyl.
  • Embodiment P202 The compound of one of Embodiments P127 to P190, wherein R 2 is unsubstituted unbranched saturated C14-C15 alkyl.
  • Embodiment P203 The compound of one of Embodiments P127 to P190, wherein R 2 is unsubstituted unbranched saturated C14-C15 alkyl.
  • Embodiment P204 The compound of any one of Embodiments P127 to P202, wherein the ligand is covalently linked to the sense strand.
  • Embodiment P205 The compound of any one of Embodiments P127 to P202, wherein the ligand is covalently linked to the sense strand.
  • Embodiment P137 wherein -L 3 -L 4 - is , the phosphate group of -L 3 -L 4 - is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, , L 5 is -NHC(O)-, R 3 is hydrogen, R 1 is unsubstituted unbranched C15 alkyl, and R 2 is unsubstituted unbranched C 15 alkyl.
  • Embodiment P206 is hydrogen, R 1 is unsubstituted unbranched C15 alkyl, and R 2 is unsubstituted unbranched C 15 alkyl.
  • Embodiment P137 wherein -L 3 -L 4 - is , the phosphate group of -L 3 -L 4 - to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, , L 5 is -NHC(O)-, R 3 is hydrogen, R 1 is unsubstituted unbranched C13 alkyl, and R 2 is unsubstituted unbranched C13 alkyl.
  • Embodiment P207 is hydrogen, R 1 is unsubstituted unbranched C13 alkyl, and R 2 is unsubstituted unbranched C13 alkyl.
  • Embodiment P137 wherein the compound is selected from DT-000429, DT-000430, DT-000431, DT-000432, DT-000735, DT-000736, DT-000737, DT-000738, DT-000776, DT-000777, DT-000778, DT-000785, DT-000786, DT-000787, DT-000828, DT-000829, DT-000830, DT-000831, and DT-000832.
  • Embodiment P208 The compound of Embodiment P137, wherein the compound is DT-000430.
  • Embodiment P209 The compound of Embodiment P137, wherein the compound is DT-000432.
  • Embodiment P210 The compound of Embodiment P137, wherein the compound is DT-000776 Embodiment P211.
  • Embodiment P212. The compound of Embodiment P211, wherein the salt is a sodium salt.
  • the compound of any one of Embodiments P1 to P212, wherein the compound is present in a pharmaceutically acceptable diluent.
  • Embodiment P214 The compound of Embodiment P213, wherein the pharmaceutically acceptable diluent is a sterile aqueous solution.
  • Embodiment P214 wherein the sterile aqueous solution is a sterile saline solution.
  • Embodiment P216. A pharmaceutical composition comprising the compound of any one of Embodiments P1 to P215.
  • Embodiment P217 A method of inhibiting the expression of neural retina leucine zipper (NRL) mRNA in a cell, comprising contacting the cell with a compound of any one of Embodiments P1 to P215, thereby inhibiting the expression of NRL mRNA in the cell.
  • Embodiment P218 The method of Embodiment P217, wherein the cell is a photoreceptor cell.
  • Embodiment P218, wherein the cell is in vitro.
  • Embodiment P220. The method of Embodiment P218, wherein the cell is in vivo.
  • Embodiment P221. A method of inhibiting the expression of neural retina leucine zipper (NRL) in a subject, comprising administering to the subject an effective amount of a compound of any one of Embodiments P1 to P215 or the pharmaceutical composition of Embodiment P216, thereby inhibiting the expression of neural retina leucine zipper (NRL) mRNA.
  • NNL neural retina leucine zipper
  • a method of treating retinitis pigmentosa comprising administering to a subject in need thereof an effective amount of a compound of any one of Embodiments P1 to P215 or the pharmaceutical composition of Embodiment P216.
  • Embodiment P223 wherein the subject is diagnosed as having retinitis pigmentosa by the presence of one or more of: a family history of retinitis pigmentosa; decreased visual acuity; abnormal retinal morphology; the presence of nyctalopia; visual field constriction; a reduced response to light stimulus; and retinal pigmentation abnormalities.
  • Embodiment P225 The method of any Embodiments P221 to P224, wherein the administration is selected from intraocular administration and topical administration.
  • Embodiment P226 The method of Embodiment P225, wherein the intraocular administration is subconjunctival administration, intravitreal administration, retrobulbar administration, or intracameral administration.
  • Embodiment P227 The method of any one of Embodiments P221 to P226, wherein the administration improves or slows the progression of one or more indicators of retinitis pigmentosa in the subject, wherein the one or more indicators is selected from visual acuity, visual acuity, retinal morphology, nyctalopia, visual field constriction, response to a light stimulus, and retinal pigmentation.
  • Embodiment P228 The method of Embodiment P227, wherein response to a light stimulus is measured by electroretinography.
  • Embodiment P229. The method of any one of Embodiments P221 to P228, comprising administering at least one additional therapy to the subject.
  • Embodiment P230 The method of any one of Embodiments P230.
  • Embodiment P23. Use of the compound of any one of Embodiments P1 to P215 for the treatment of retinitis pigmentosa.
  • Embodiment P232. Use of the pharmaceutical composition of Embodiment P216 for the treatment of retinitis pigmentosa.
  • Embodiment P233. The compound of Embodiment P27, wherein the nucleotide sequence of the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 213, 215, 217, 224, 241, 226, 228, and 230.
  • Embodiment P234 The compound of Embodiment P233, wherein the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236.
  • Embodiment P235 Embodiment P235.
  • Embodiment P233 wherein the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 213, 215, 217, 224, 241, 226, 228, and 230.
  • Embodiment P236 is a nucleotide sequence selected from SEQ ID NO: 213, 215, 217, 224, 241, 226, 228, and 230.
  • the compound of Embodiment P233 wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 213, 215, 217, 224, 241, 226, 228, and 230, and wherein the nucleotide sequence of the antisense strand is 100% complementary to 23 contiguous nucleotides of SEQ ID NO: 1.
  • Embodiment P237 wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 213, 215, 217, 224, 241, 226, 228, and 230, and wherein the nucleotide sequence of the antisense strand is 100% complementary to 23 contiguous nucleotides of SEQ ID NO: 1.
  • Embodiment P237 Embodiment P237.
  • nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236.
  • SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236 Embodiment P238.
  • Embodiment P240 Embodiment P240.
  • the sense strand is 21 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236, and wherein the nucleotide sequence of the sense strand is identical to 21 contiguous nucleotides of SEQ ID NO: 1.
  • nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 268 and 269.
  • Embodiment P242. The compound of any one of Embodiments P45 to P49, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 268 and 269.
  • Embodiment P244. The compound of any one of Embodiments P45 to P49, wherein the sense strand is 21 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 268 and 269, and wherein the nucleotide sequence of the sense strand is identical to a 21 contiguous nucleotides of SEQ ID NO: 1.
  • the compound of any one of Embodiments P63 to P67, wherein the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of SEQ ID NO: 237.
  • the compound of any one of Embodiments P63 to P67, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to the nucleotide sequence of SEQ ID NO: 237.
  • Embodiment P248 The compound of any one of Embodiments P63 to P67, wherein the sense strand is 21 nucleotides in length and comprises nucleotides 1 to 19 of the nucleotide sequence of SEQ ID NO: 237, and wherein the nucleotide sequence of the sense strand is identical to 21 contiguous nucleotides of SEQ ID NO: 1.
  • the compound of any one of Embodiments P72 to P76, wherein the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 238, 270, 271, 272, and 273.
  • the compound of any one of Embodiments P72 to P76, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 238, 270, 271, 272, and 273.
  • Embodiment P252 The compound of any one of Embodiments P72 to P76, wherein the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 238, 270, 271, 272, and 273.
  • the compound of any one of Embodiments P233 to P252, wherein the nucleotide sequence of the antisense strand is at least 95% complementary to SEQ ID NO: 1.
  • Embodiment P233 to P252 wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1.
  • Embodiment P255. The compound of any one of Embodiments P233 to P254, wherein the antisense strand and the sense strand are not covalently linked.
  • Embodiment P256. The compound of any one of Embodiments P233 to P255, wherein the hybridization of the antisense strand to the sense strand forms at least one blunt end.
  • Embodiment P257 The compound of Embodiment P256, wherein the hybridization of the antisense strand to the sense strand forms a blunt end at each terminus of the compound.
  • Embodiment P2 The compound of any one of Embodiments P233 to P256, wherein at least one strand comprises a 3’ nucleotide overhang of one to five nucleotides.
  • Embodiment P259. The compound of Embodiment P258, wherein the sense strand comprises the 3’ nucleotide overhang.
  • Embodiment P260. The compound of Embodiment P258, wherein the antisense strand comprises the 3’ nucleotide overhang.
  • Embodiment P261. The compound of Embodiment P258, wherein each of the sense strand and the antisense strand comprises a 3’ nucleotide overhang of one to five nucleotides.
  • each nucleotide of the 3’ nucleotide overhang of the antisense strand is complementary to SEQ ID NO: 1.
  • the compound of Embodiment P260 or P261, wherein each nucleotide of the 3’ nucleotide overhang of the antisense strand is not complementary to SEQ ID NO: 1 Embodiment P264.
  • the compound of any one of Embodiments P258 to P263, wherein each nucleotide of the 3’ nucleotide overhang is a deoxythymidine.
  • Embodiment P258 to P264 wherein the 3’ nucleotide overhang is two nucleotides in length.
  • Embodiment P266. The compound of any one of Embodiments P233 to P265, wherein at least one nucleotide of the antisense strand is a modified nucleotide.
  • Embodiment P267. The compound of any one of Embodiments P233 to P266, wherein at least one nucleotide of the sense strand is a modified nucleotide.
  • Embodiment P268 is a modified nucleotide.
  • each nucleotide of the antisense strand forming the double-stranded region is a modified nucleotide.
  • Embodiment P269. The compound of any one of Embodiments P233 to P268, wherein each nucleotide of the sense strand forming the double-stranded region is a modified nucleotide.
  • Embodiment P270. The compound of any one of Embodiments P266 to P269, wherein the modified nucleotide comprises one or more of a modified sugar moiety, a modified internucleotide linkage, and a 5’-terminal modified phosphate group.
  • the compound of Embodiment P270, wherein the modified nucleotide comprising a modified sugar moiety is selected from a 2’-fluoro nucleotide, a 2’- O-methyl nucleotide, a 2’-O-methoxyethyl nucleotide, and a bicyclic sugar nucleotide.
  • Embodiment P272. The compound of Embodiment P270, wherein the modified internucleotide linkage is a phosphorothioate internucleotide linkage.
  • Embodiment P272 wherein the first two internucleotide linkages at the 5’ terminus of the sense strand and the last two internucleotide linkages at the 3’ terminus of the sense strand are phosphorothioate internucleotide linkages.
  • Embodiment P274. The compound of Embodiment P273, wherein the first two internucleotide linkages at the 5’ terminus of the antisense strand and the last two internucleotide linkages at the 3’ terminus of the antisense strand are phosphorothioate internucleotide linkages.
  • Embodiment P275 wherein the first two internucleotide linkages at the 5’ terminus of the antisense strand and the last two internucleotide linkages at the 3’ terminus of the antisense strand are phosphorothioate internucleotide linkages.
  • Embodiment P271 wherein the covalent linkage of the bicyclic sugar is selected from a 4’-CH(CH 3 )-O-2’ linkage, a 4'-(CH 2 ) 2 -O-2' linkage, a 4'-CH(CH 2 -OMe)-O-2' linkage, 4’-CH 2 -N(CH 3 )-O-2’ linkage, and 4’-CH 2 -N(H)- O-2’ linkage.
  • Embodiment P276 The compound of Embodiment P270, wherein the 5’-terminal modified phosphate group is a 5’-(E)-vinylphosphonate.
  • Embodiment P277 wherein the 5’-terminal modified phosphate group is a 5’-(E)-vinylphosphonate.
  • nucleotides 1 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O- methylnucleotides
  • nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-flouronucleotides
  • nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides
  • the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages
  • each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P278 The compound of any one of Embodiments P233 to P276, wherein the antisense strand is 19 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O- methylnucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-flouronucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P279. The compound of Embodiment P277 or P278, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides, and nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P280 The compound of Embodiment P277 or P278, wherein the sense strand is 19 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoro nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P281 The compound of any one of Embodiments P233 to P276, wherein the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methylnucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’- flouronucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P282 The compound of Embodiment P281, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P283 The compound of Embodiment P281, wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta- D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P284 The compound of Embodiment P281, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P285. The compound of any one of Embodiments P233 to P276, wherein the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methylnucleotides and nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’- flouronucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P286 The compound of Embodiment P285, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P287 The compound of Embodiment P285, wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta-D- deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P288 The compound of any one of Embodiments P233 to P276, wherein the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methylnucleotides and nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’- flouronucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P289 The compound of Embodiment P288, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-O-methyl nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P290 The compound of Embodiment P288, wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta-D- deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage.
  • Embodiment P291 The compound of any one of Embodiments P233 to P290, wherein the compound comprises a ligand covalently linked to the double-stranded nucleic acid.
  • Embodiment P292. The compound of Embodiment P291, wherein the compound has the structure: wherein A is the double-stranded nucleic acid; wherein t is an integer from 1 to 5; L 3 and L 4 are independently a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO2-O-, -O-P(O)(S
  • Embodiment P293 The compound of Embodiment P292, wherein t is 1. Embodiment P294.
  • the compound of Embodiment P292, wherein t is 2.
  • the compound of Embodiment P292, wherein t is 3.
  • the compound of any one of Embodiments P292 to P295, wherein A is the sense strand.
  • Embodiment P297. The compound of any one of Embodiments P292 to P296, wherein A is the antisense strand.
  • Embodiment P292 The compound of one of Embodiments P292 to P297, wherein each of R 23 , R 24 and R 25 is independently hydrogen or unsubstituted C1-C3 alkyl.
  • Embodiment P299. The compound of one of Embodiments P292 to P298, wherein one L 3 is attached to a 3’ carbon of a nucleotide.
  • Embodiment P300. The compound of Embodiment P299, wherein the 3’ carbon is the 3’ carbon of a 3’ terminal nucleotide.
  • Embodiment P301 The compound of one of Embodiments P292 to P300, wherein one L 3 is attached to a 5’ carbon of a nucleotide.
  • Embodiment P301 wherein the 5’ carbon is the 5’ carbon of a 5’ terminal nucleotide.
  • Embodiment P303. The compound of one of Embodiments P292 to P302, wherein one L 3 is attached to a 2’ carbon of a nucleotide.
  • Embodiment P305 The compound of one of Embodiments P292 to P304, wherein L 3 is independently .
  • Embodiment P306. The compound of one of Embodiments P292 to P304, wherein L 3 is independently OPO2O or –OP(O)(S)O.
  • Embodiment P307. The compound of one of Embodiments P292 to P304, wherein L 3 is independently –O-.
  • Embodiment P308. The compound of any one of Embodiments P292 to P304, wherein L 3 is independently -C(O)-.
  • Embodiment P310 The compound of any one of Embodiments P292 to P304, wherein L 3 is independently -O-P(O)(N(CH3)2)-N-.
  • Embodiment P310 The compound of one of Embodiments P292 to P309, wherein L 4 is independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.
  • Embodiment P311 The compound of one of Embodiments P292 to P310, wherein L 4 is independently –L 7 -NH-C(O)- or –L 7 -C(O)-NH-, wherein L 7 is substituted or unsubstituted alkylene.
  • Embodiment P313. The compound of one of Embodiments P292 to P311, wherein L 4 is independently .
  • Embodiment P314. The compound of one of Embodiments P292 to P313, wherein –L 3 -L 4 - is independently –O-L 7 -NH-C(O)- or –O-L 7 -C(O)-NH-, wherein L 7 is independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene.
  • Embodiment P314 wherein –L 3 -L 4 - is independently –O-L 7 -NH-C(O)-, wherein L 7 is independently substituted or unsubstituted C5- C 8 alkylene.
  • Embodiment P316 The compound of Embodiment P315, wherein –L 3 -L 4 - is .
  • Embodiment P317 The compound of Embodiment P314, wherein –L 3 -L 4 - is independently –O-L 7 -NH-C(O)-, wherein L 7 is independently substituted or unsubstituted C5- C 8 alkylene.
  • Embodiment P317 wherein –L 3 -L 4 - is independently OPO2OL 7 -NH-C(O)- or –OP(O)(S)OL 7 -NH-C(O)-, wherein L 7 is independently substituted or unsubstituted C 5 -C 8 alkylene.
  • Embodiment P319. The compound of Embodiment P318, wherein –L 3 -L 4 - is Embodiment P320.
  • Embodiment P319 wherein an –L 3 -L 4 - is terminal nucleotide.
  • Embodiment P322. The compound of Embodiment P319, wherein an –L 3 -L 4 - is attached to a 2’ carbon.
  • Embodiment P323. The compound of one of Embodiments P292 to P322, wherein R 3 is independently hydrogen.
  • Embodiment P324. The compound of one of Embodiments P292 to P323, wherein L 6 is independently NHC(O), –C(O)NH-,substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • Embodiment P324, wherein L 6 is independently -NHC(O)-.
  • Embodiment P326 The compound of Embodiment P324, wherein L 6A is independently a bond or unsubstituted alkylene; L 6B is independently a bond, -NHC(O)-, or unsubstituted arylene; L 6C is independently a bond, unsubstituted alkylene, or unsubstituted arylene; L 6D is independently a bond or unsubstituted alkylene; and L 6E is independently a bond or -NHC(O)-.
  • Embodiment P327 The compound of Embodiment P324, wherein L 6 is independently -NHC(O)-.
  • Embodiment P324 wherein L 6A is independently a bond or unsubstituted C 1 -C 8 alkylene; L 6B is independently a bond, -NHC(O)-, or unsubstituted phenylene; L 6C is independently a bond, unsubstituted C2-C8 alkynylene, or unsubstituted phenylene; L 6D is independently a bond or unsubstituted C 1 -C 8 alkylene; and L 6E is independently a bond or -NHC(O)-.
  • Embodiment P328 The compound of one of Embodiments P292 to P323, wherein Embodiment P329.
  • Embodiment P331 The compound of one of Embodiments P292 to P328, wherein L 5 is independently NHC(O), –C(O)NH-,substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • Embodiment P330 The compound of one of Embodiments P292 to P328, wherein L 5 is independently -NHC(O)-.
  • L 5A is independently a bond or unsubstituted alkylene
  • L 5B is independently a bond, -NHC(O)-, or unsubstituted arylene
  • L 5C is independently a bond, unsubstituted alkylene, or unsubstituted arylene
  • L 5D is independently a bond or unsubstituted alkylene
  • L 5E is independently a bond or -NHC(O)-.
  • Embodiment P333 The compound of one of Embodiments P292 to P328, wherein L 5A is independently a bond or unsubstituted C1-C8 alkylene; L 5B is independently a bond, -NHC(O)-, or unsubstituted phenylene; L 5C is independently a bond, unsubstituted C2-C8 alkynylene, or unsubstituted phenylene; L 5D is independently a bond or unsubstituted C 1 -C 8 alkylene; and L 5E is independently a bond or -NHC(O)-.
  • Embodiment P333 The compound of one of Embodiments P292 to P328, wherein Embodiment P334.
  • Embodiment P335 The compound of one of Embodiments P292 to P333, wherein R 1 is unsubstituted C 1 -C 17 alkyl.
  • Embodiment P335. The compound of one of Embodiments P292 to P333, wherein R 1 is unsubstituted C 11 -C 17 alkyl.
  • Embodiment P336 The compound of one of Embodiments P292 to P333, wherein R 1 is unsubstituted C13-C17 alkyl.
  • Embodiment P337 The compound of one of Embodiments P292 to P333, wherein R 1 is unsubstituted C 14 -C 15 alkyl.
  • Embodiment P33 The compound of one of Embodiments P292 to P333, wherein R 1 is unsubstituted unbranched C1-C17 alkyl.
  • Embodiment P339. The compound of one of Embodiments P292 to P333, wherein R 1 is unsubstituted unbranched C 11 -C 17 alkyl.
  • Embodiment P340. The compound of one of Embodiments P292 to P333, wherein R 1 is unsubstituted unbranched C 13 -C 17 alkyl.
  • Embodiment P341 The compound of one of Embodiments P292 to P333, wherein R 1 is unsubstituted unbranched C14-C15 alkyl.
  • Embodiment P343 The compound of one of Embodiments P292 to P333, wherein R 1 is unsubstituted unbranched saturated C 1 -C 17 alkyl.
  • Embodiment P343 The compound of one of Embodiments P292 to P333, wherein R 1 is unsubstituted unbranched saturated C11-C17 alkyl.
  • Embodiment P344 The compound of one of Embodiments P292 to P333, wherein R 1 is unsubstituted unbranched saturated C13-C17 alkyl.
  • Embodiment P345. The compound of one of Embodiments P292 to P333, wherein R 1 is unsubstituted unbranched saturated C 14 -C 15 alkyl.
  • Embodiment P346 The compound of one of Embodiments P292 to P333, wherein R 1 is unsubstituted unbranched saturated C 14 -C 15 alkyl.
  • Embodiment P351 The compound of one of Embodiments P292 to P345, wherein R 2 is unsubstituted unbranched C 1 -C 17 alkyl.
  • Embodiment P352 The compound of one of Embodiments P292 to P345, wherein R 2 is unsubstituted unbranched C11-C17 alkyl.
  • Embodiment P352 The compound of one of Embodiments P292 to P345, wherein R 2 is unsubstituted unbranched C13-C17 alkyl.
  • Embodiment P353 The compound of one of Embodiments P292 to P345, wherein R 2 is unsubstituted unbranched C 14 -C 15 alkyl.
  • Embodiment P357 The compound of one of Embodiments P292 to P345, wherein R 2 is unsubstituted unbranched saturated C14-C15 alkyl. Embodiment P358.
  • Embodiment P357 The compound of any one of Embodiments P292 to P357, wherein the ligand is covalently linked to the antisense strand.
  • Embodiment P359. The compound of any one of Embodiments P292 to P358, wherein the ligand is covalently linked to the sense strand.
  • Embodiment P292 wherein -L 3 -L 4 - , the phosphate group of -L 3 -L 4 - is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, , L 5 is -NHC(O)-, R 3 is hydrogen, R 1 is unsubstituted unbranched C15 alkyl, and R 2 is unsubstituted unbranched C15 alkyl.
  • Embodiment P292 wherein -L 3 -L 4 - is , the phosphate group of -L 3 -L 4 - to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, , L 5 is -NHC(O)-, R 3 is hydrogen, R 1 is unsubstituted unbranched C13 alkyl, and and R 2 is unsubstituted unbranched C 13 alkyl.
  • Embodiment P362 The compound of Embodiment P292, wherein the compound is selected from DT-001373, DT-001374, DT-001375, and DT-001386.
  • Embodiment P292 wherein the compound is DT-001373.
  • Embodiment P364. The compound of Embodiment P292, wherein the compound is DT-001374.
  • Embodiment P365 The compound of Embodiment P292, wherein the compound is DT-001375.
  • Embodiment P366. The compound of Embodiment P292, wherein the compound is DT-001386.
  • Embodiment P367 The compound of any one of Embodiments P233 to P366, wherein the compound is present as a pharmaceutical salt.
  • Embodiment P368. The compound of Embodiment P367, wherein the salt is a sodium salt.
  • Embodiment P370 The compound of any one of Embodiments P233 to P368, wherein the compound is present in a pharmaceutically acceptable diluent.
  • the compound of Embodiment P369, wherein the pharmaceutically acceptable diluent is a sterile aqueous solution.
  • the compound of Embodiment P370, wherein the sterile aqueous solution is a sterile saline solution.
  • Embodiment P372. A pharmaceutical composition comprising the compound of any one of Embodiments P233 to P371.
  • a method of inhibiting the expression of neural retina leucine zipper (NRL) mRNA in a cell comprising contacting the cell with a compound of any one of Embodiments P233 to P371, thereby inhibiting the expression of NRL mRNA in the cell.
  • Embodiment P374. The method of Embodiment P373, wherein the cell is a photoreceptor cell.
  • Embodiment P375. The method of Embodiment P373, wherein the cell is in vitro.
  • Embodiment P376 The method of Embodiment P373, wherein the cell is in vivo.
  • Embodiment P377 A method of inhibiting the expression of neural retina leucine zipper (NRL) mRNA in a cell, comprising contacting the cell with a compound of any one of Embodiments P233 to P371, thereby inhibiting the expression of NRL mRNA in the cell.
  • Embodiment P374. The method of Embodiment P373, wherein the cell is
  • a method of inhibiting the expression of neural retina leucine zipper (NRL) in a subject comprising administering to the subject an effective amount of a compound of any one of Embodiments P233 to P371 or the pharmaceutical composition of Embodiment P372, thereby inhibiting the expression of neural retina leucine zipper (NRL) mRNA.
  • Embodiment P378. A method of treating retinitis pigmentosa, comprising administering to a subject in need thereof an effective amount of a compound of any one of Embodiments P233 to P371 or the pharmaceutical composition of Embodiment P372.
  • Embodiment P381. The method of any one of Embodiments P377 to P380, wherein the administration is selected from intraocular administration and topical administration.
  • Embodiment P381 wherein the intraocular administration is subconjunctival administration, intravitreal administration, retrobulbar administration, or intracameral administration.
  • Embodiment P383. The method of any one of Embodiments P377 to P382, wherein the administration improves or slows the progression of one or more indicators of retinitis pigmentosa in the subject, wherein the one or more indicators is selected from visual acuity, visual acuity, retinal morphology, nyctalopia, visual field constriction, response to a light stimulus, and retinal pigmentation.
  • Embodiment P384. The method of Embodiment P383, wherein response to a light stimulus is measured by electroretinography.
  • Embodiment P377 to P384 comprising administering at least one additional therapy to the subject.
  • Embodiment P386 Use of the compound of any one of Embodiments P233 to P371 in therapy.
  • Embodiment P387. Use of the compound of any one of Embodiments P233 to P371 for the treatment of retinitis pigmentosa.
  • Embodiment P388. Use of the pharmaceutical composition of Embodiment P372 for the treatment of retinitis pigmentosa. Additional embodiments Embodiment Q1.
  • a compound comprising an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein each of the antisense strand and sense strands is 15 to 25 nucleotides in length, the nucleotide sequence of the antisense strand is at least 90% complementary to the nucleotide sequence of the NRL mRNA (SEQ ID NO: 1), and the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand.
  • SEQ ID NO: 1 the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand.
  • each of the antisense strand and sense strands is 15 to 25 nucleotides in length
  • the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 contiguous nucleotides of any one of nucleotides 501 to 563 of SEQ ID NO: 1, nucleotides 602 to 626 of SEQ ID NO: 1, nucleotides 623 to 654 of SEQ ID NO: 1, nucleotides 684 to 710 of SEQ ID NO: 1, nucleotides 741 to 765 of SEQ ID NO: 1, nucleotides 759 to 777 of SEQ ID NO: 1, nucleotides 882 to 909 of SEQ ID NO: 1, or nucleotides 1111 to 1133 of SEQ ID NO: 1, and the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand.
  • Embodiment Q3 The compound of Embodiment Q1 or Q2, wherein i. the antisense strand is 19 to 21 nucleotides in length; or ii. the antisense strand is 21 to 23 nucleotides in length.
  • Embodiment Q4 The compound of any one of Embodimens Q1 to Q3, wherein i. the sense strand is 17 to 23 nucleotides in length; ii. the sense strand is 19 to 21 nucleotides in length; or iii. the sense strand is 21 to 23 nucleotides in length.
  • Embodiment Q5. The compound of any one of Embodiments Q1 to Q4, wherein i.
  • the double-stranded region is 19 nucleotide pairs in length; ii. the double-stranded region is 20 nucleotide pairs in length; or iii. the double-stranded region is 21 nucleotide pairs in length.
  • Embodiment Q6 The compound of any one of Embodiments Q1 to Q5, wherein the nucleotide sequence of the sense strand has no more than one mismatch to the nucleotide sequence of the antisense strand.
  • Embodiment Q7 The compound of any one of Embodiments Q1 to Q6, wherein the nucleotide sequence of the sense strand has no mismatches to the nucleotide sequence of the antisense strand.
  • Embodiment Q8 The compound of any one of Embodiments Q1 to Q5, wherein the nucleotide sequence of the sense strand has no mismatches to the nucleotide sequence of the antisense strand.
  • nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1.
  • nucleotides 501 to 563 of SEQ ID NO: 1. Embodiment Q9.
  • nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1.
  • nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1.
  • nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1.
  • nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1.
  • nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1.
  • nucleotides 684 to 710 of SEQ ID NO: 1. Embodiment Q12.
  • nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1.
  • nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, or 19 contiguous nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1.
  • Embodiment Q7 The compound of any one of Embodiments Q1 to Q7, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or 23 contiguous nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1.
  • Embodiment Q15 The compound of any one of Embodiments Q1 to Q14, wherein the antisense strand and the sense strand are not covalently linked.
  • Embodiment Q16 The compound of any one of Embodiments Q1 to Q15, wherein at least one strand comprises a 3’ nucleotide overhang of one to five nucleotides.
  • Embodiment Q17 The compound of any one of Embodiments Q1 to Q7, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19,
  • Embodiment Q16 wherein the sense strand comprises the 3’ nucleotide overhang.
  • Embodiment Q18 The compound of Embodiment Q16, wherein the antisense strand comprises the 3’ nucleotide overhang.
  • Embodiment Q19 The compound of any one of Embodiments Q16 to Q18, wherein each nucleotide of the 3’ nucleotide overhang of the antisense strand is complementary to SEQ ID NO: 1.
  • Embodiment Q20 The compound of any one of Embodiments Q16 to Q19, wherein the 3’ nucleotide overhang is two nucleotides in length. Embodiment Q21.
  • each nucleotide of the antisense strand forming the double-stranded region is a modified nucleotide.
  • Embodiment Q22 The compound of any one of Embodiments Q1 to Q21, wherein each nucleotide of the sense strand forming the double-stranded region is a modified nucleotide.
  • Embodiment Q23 The compound of Embodiment Q21 or Q22, wherein the modified nucleotide comprises one or more of a modified sugar moiety, a modified internucleotide linkage, and a 5’-terminal modified phosphate group.
  • Embodiment Q24 The compound of any one of Embodiments Q1 to Q20, wherein each nucleotide of the antisense strand forming the double-stranded region is a modified nucleotide.
  • the compound of Embodiment Q23, wherein the modified nucleotide comprising a modified sugar moiety is selected from a 2’-fluoro nucleotide, a 2’-O-methyl nucleotide, a 2’-O-methoxyethyl nucleotide, and a bicyclic sugar nucleotide.
  • the compound of Embodiment Q23, wherein the modified internucleotide linkage is a phosphorothioate internucleotide linkage.
  • Embodiment Q26 is a phosphorothioate internucleotide linkage.
  • Embodiment Q25 wherein the first two internucleotide linkages at the 5’ terminus of the sense strand and the last two internucleotide linkages at the 3’ terminus of the sense strand are phosphorothioate internucleotide linkages.
  • Embodiment Q27 The compound of Embodiment Q26, wherein the first two internucleotide linkages at the 5’ terminus of the antisense strand and the last two internucleotide linkages at the 3’ terminus of the antisense strand are phosphorothioate internucleotide linkages.
  • Embodiment Q28 wherein the first two internucleotide linkages at the 5’ terminus of the antisense strand and the last two internucleotide linkages at the 3’ terminus of the antisense strand are phosphorothioate internucleotide linkages.
  • Embodiment Q29 The compound of Embodiment Q28, wherein the compound has the structure: wherein A is the double-stranded nucleic acid; wherein t is an integer from 1 to 5; L 3 and L 4 are independently a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO2-O-, -O-P(O)(S)-O-, -O-P
  • Embodiment Q30 The compound of Embodiment Q29, wherein (i) t is 1; (ii) t is 2; or (iii) t is 3.
  • Embodiment Q31 The compound of Embodiment Q29, wherein A is the sense strand of the double-stranded nucleic acid.
  • Embodiment Q32 The compound of Embodiment Q29, wherein A is the sense strand of the double-stranded nucleic acid.
  • Embodiment Q31 wherein -L 3 -L 4 - the phosphate group of -L 3 -L 4 - is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, , L 5 is -NHC(O)-, R 3 is hydrogen, R 1 is unsubstituted unbranched C15 alkyl, and R 2 is unsubstituted unbranched C 15 alkyl.
  • Embodiment Q33 is hydrogen, R 1 is unsubstituted unbranched C15 alkyl, and R 2 is unsubstituted unbranched C 15 alkyl.
  • Embodiment Q31 wherein -L 3 -L 4 - is , the phosphate group of -L 3 -L 4 - to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, , L 5 is -NHC(O)-, R 3 is hydrogen, R 1 is unsubstituted unbranched C13 alkyl, and and R 2 is unsubstituted unbranched C 13 alkyl.
  • Embodiment Q31 wherein the compound is selected from DT-000429, DT-000430, DT-000431, DT-000432, DT-000735, DT- 000736, DT-000737, DT-000738, DT-000776, DT-000777, DT-000778, DT-000785, DT-000786, DT-000787, DT-000828, DT-000829, DT-000830, DT-000831, DT-000832, DT-001373, DT-001374, DT-001375, and DT-001386.
  • Embodiment Q35 The compound of Embodiment Q31, wherein the compound is DT-000430.
  • Embodiment Q36 The compound of Embodiment Q31, wherein the compound is DT-000432.
  • Embodiment Q37 The compound of Embodiment Q31, wherein the compound is DT-000776.
  • Embodiment Q38 The compound of Embodiment Q31, wherein the compound is DT-001373.
  • Embodiment Q39 The compound of Embodiment Q31, wherein the compound is DT-001374.
  • Embodiment Q40 The compound of Embodiment Q31, wherein the compound is DT-001375.
  • Embodiment Q41 The compound of Embodiment Q31, wherein the compound is DT-001386.
  • Embodiment Q42 The compound of Embodiment Q31, wherein the compound is DT-001386.
  • Embodiment Q43 The compound of Embodiment Q42, wherein the salt is a sodium salt.
  • Embodiment Q44. The compound of any one of Embodiments Q1 to Q43, wherein the compound is present in a pharmaceutically acceptable diluent.
  • Embodiment Q45. The compound of Embodiment Q44, wherein the pharmaceutically acceptable diluent is a sterile aqueous solution.
  • Embodiment Q46. The compound of Embodiment Q45, wherein the sterile aqueous solution is a sterile saline solution.
  • a pharmaceutical composition comprising the compound of any one of Embodiments Q1 to Q46.
  • Embodiment Q48. A method of inhibiting the expression of neural retina leucine zipper (NRL) mRNA in a cell, comprising contacting the cell with a compound of any one of Embodiments Q1 to Q46, thereby inhibiting the expression of NRL mRNA in the cell.
  • Embodiment Q49. The method of Embodiment Q48, wherein the cell is a photoreceptor cell.
  • Embodiment Q50 The method of Embodiment Q49, wherein the cell is in vitro.
  • Embodiment Q51. The method of Embodiment Q49, wherein the cell is in vivo.
  • a method of inhibiting the expression of neural retina leucine zipper (NRL) in a subject comprising administering to the subject an effective amount of a compound of any one of Embodiments Q1 to Q46 or the pharmaceutical composition of Embodiment Q47, thereby inhibiting the expression of neural retina leucine zipper (NRL) mRNA.
  • Embodiment Q53. A method of treating retinitis pigmentosa, comprising administering to a subject in need thereof an effective amount of a compound of any one of Embodiments Q1 to Q46 or the pharmaceutical composition of Embodiment Q47.
  • Embodiment Q54 A method of inhibiting the expression of neural retina leucine zipper (NRL) in a subject, comprising administering to the subject an effective amount of a compound of any one of Embodiments Q1 to Q46 or the pharmaceutical composition of Embodiment Q47.
  • Embodiment Q52 or Q53 wherein prior to administration of the compound, the subject has been diagnosed as having retinitis pigmentosa.
  • Embodiment Q55 The method of Embodiment Q54, wherein the subject is diagnosed as having retinitis pigmentosa by the presence of one or more of: a family history of retinitis pigmentosa; decreased visual acuity; abnormal retinal morphology; the presence of nyctalopia; visual field constriction; a reduced response to light stimulus; and retinal pigmentation abnormalities.
  • Embodiment Q56 The method of any one of Embodiments Q52 to Q55, wherein the administration is selected from intraocular administration and topical administration.
  • Embodiment Q57 The method of any one of Embodiments Q52 to Q55, wherein the administration is selected from intraocular administration and topical administration.
  • Embodiment Q56 wherein the intraocular administration is subconjunctival administration, intravitreal administration, retrobulbar administration, or intracameral administration.
  • Embodiment Q58 The method of any one of Embodiments Q52 to Q57, wherein the administration improves or slows the progression of one or more indicators of retinitis pigmentosa in the subject, wherein the one or more indicators is selected from visual acuity, visual acuity, retinal morphology, nyctalopia, visual field constriction, response to a light stimulus, and retinal pigmentation.
  • Embodiment Q59 The method of Embodiment Q58, wherein response to a light stimulus is measured by electroretinography.
  • Embodiment Q60 The method of Embodiment Q60.
  • Embodiment Q52 to Q59 comprising administering at least one additional therapy to the subject.
  • Embodiment Q61 Use of the compound of any one of Embodiments Q1 to Q46 in therapy.
  • Embodiment Q62 Use of the compound of any one of Embodiments Q1 to Q46 for the treatment of retinitis pigmentosa.
  • Embodiment Q63 Use of the pharmaceutical composition of Embodiment Q47 for the treatment of retinitis pigmentosa. Examples The following examples are presented to more fully illustrate some embodiments of the invention. They should not be construed, however, as limiting the scope of the invention.
  • Example 1 Conjugation of Uptake Motifs to Oligonucleotides
  • Scheme I Conjugation of Uptake Motifs to the 3’ Carbon of the 3’ Terminal Nucleotide of an Scheme I above illustrates the preparation of an oligonucleotide conjugated with a lipid moiety at the 3’ terminus of the oligonucleotide, i.e. at the 3’ carbon of the terminal 3’ nucleotide.
  • 3’-amino CPG beads I-1 (Glen Research, Catalog No.20-2958) modified with the DMT and Fmoc-protected C7 linker illustrated above were treated with 20% piperidine/DMF to afford Fmoc-deprotected amino C7 CPG beads I-2.
  • Lipid motif DTx-01-08 was then coupled to I-2 using HATU and DIEA in DMF to produce lipid-loaded CPG beads I-3, which were treated by 3% dichloroacetic acid (DCA) in DCM to remove the DMT protecting group and afford I-4.
  • Oligonucleotide synthesis was accomplished via standard phosphoramidite chemistry and yielded oligonucleotide-bounded CPG beads I-5.
  • beads I-5 containing methyl ester-protected lipid motifs were saponified to their respective carboxylic acid using 0.5 M LiOH in 3:1 v/v methanol/water.
  • Subsequent treatment of I-5 with AMA [ammonium hydroxide (28%)/methylamine (40%) (1:1, v/v)] cleaved the DTx-01-08-conjugated oligonucleotide from the beads.
  • the conjugated oligonucleotide was then purified by RP-HPLC and characterized by MALDI-TOF MS using the [M+H] peak.
  • DTx-01-08 was then coupled to II-2 using HATU and DIEA in DMF to produce the fatty-acid loaded CPG beads II-3, which were subsequently treated with 3% dichloroacetic acid (DCA) in DCM to remove the DMT protecting group and afford II-4.
  • Oligonucleotide synthesis was performed on II-4 via standard phosphoramidite chemistry. The final coupling was with a phosphoramidite (Glen Research, Catalog No.10-1906) that incorporated a monomethoxytrityl (MMTr) protected 6-carbon alkyl amine as shown in structure II-5.
  • MMTr monomethoxytrityl
  • II-6 was coupled to DTx-01-08 using HATU and DIEA in DMF to yield II-7.
  • Stepwise deprotection with triethylamine in acetonitrile to remove phosphate protecting groups
  • AMA ammonium hydroxide (28%)/methylamine (40%) (1:1, v/v)] (to remove base protecting groups and cleave the oligonucleotide from the synthesis resin) yielded crude II-8.
  • Purification using RP-HPLC yielded a conjugated oligonucleotide.
  • Scheme III Conjugation of an Uptake Motif to the 5’ Terminus of an Oligonucleotide Scheme III above illustrates the preparation of an oligonucleotide conjugated to an uptake motif at the 5’ terminus, i.e. at the 5’ carbon of the 3’ terminal nucleotide.
  • oligonucleotide synthesis was performed on CPG beads III-1 (Glen Research, Catalog No.20-5041-xx) via standard phosphoramidite chemistry.
  • the oligonucleotide was then purified by RP-HPLC and characterized by MALDI-TOF MS using the [M+H] peak.
  • Duplex Formation For each of the oligonucleotides synthesized by Schemes I, II, or III and listed above, the corresponding complementary strand was prepared via standard phosphoramidite chemistry, purified by IE-HPLC, and characterized by MALDI-TOF MS using the [M+H] peak.
  • the duplex was formed by mixing equal molar equivalents of the passenger strand (the sense strand) and guide strand (the antisense strand), heating to 90°C for 5 minutes, and then slowly cooling to room temperature. Duplex formation was confirmed by non-denaturing PAGE or non-denaturing HPLC.
  • HEK293 cells were purchased from ATCC and were cultured in DMEM containing 10% Fetal Bovine Serum (FBS), 2 mM L-glutamine, 1X non-essential amino acids, 100 U/mL penicillin and 100 mg/mL streptomycin in a humidified 37°C incubator with 5% CO2.
  • FBS Fetal Bovine Serum
  • 2 mM L-glutamine 1X non-essential amino acids
  • 100 U/mL penicillin and 100 mg/mL streptomycin in a humidified 37°C incubator with 5% CO2.
  • Generation of Stable Human and Mouse NRL Cell Lines.3x10 ⁇ 6 HEK293 cells were plated onto 10-cm tissue culture treated petri dishes in the media described herein without antibiotics. The day after plating, human or mouse NRL plasmids were transfected into HEK293 cells with Lipofectamine 2000 according to the manufacturer’s protocol.
  • each plasmid were diluted in 480 uL of DMEM without FBS or antibiotic.
  • 50 uL of Lipofectamine 2000 was diluted in 450 uL of DMEM without FBS or antibiotic.
  • the plasmid/DMEM and the Lipofectamine 2000/DMEM cocktails were then combined, mixed by titrating up and down and incubated for 20 minutes at room temperature to enable complex formation.
  • the DMEM media containing FBS but lacking antibiotic (9 mL) was then added to the plasmid/Lipofectamine 2000 complexes (1 mL) and then added to cells in the 10-cm dish. The cells were incubated overnight at 37°C in the incubator.
  • HEK293 cells were trypsinized and diluted to 20,000 cells/well, in 90 uL of antibiotic-free media. Compounds were diluted in PBS to 100x of the desired final concentration.
  • Lipofectamine RNAiMax (Life Technologies) was diluted 1:66.7 in media lacking supplements (e.g. FBS, antibiotic etc.). The 100x compound in PBS was then complexed with RNAiMAX by adding 1 part compound in PBS to 9 parts lipofectamine/media. Following incubation for 20 minutes, 10 uL of the compound:RNAiMAX complexes were added to a 96 well collagen coated plate. A volume of 90 ul of the cell dilution was added to each well of the 96-well plate. The plate was then placed in a humidified 37°C incubator with 5% CO 2 .
  • media lacking supplements e.g. FBS, antibiotic etc.
  • Real-time quantitative PCR was performed utilizing gene-specific primers (Thermofisher Scientific; IDTDNA), TaqMan probes (Thermofisher Scientific; IDTDNA) and TaqMan fast universal PCR master mix (Thermofisher scientific) on a StepOnePlus real-time PCR system (Thermofisher Scientific) according to the manufacturer’s instructions.
  • mRNA expression was normalized to the expression of either 18s rRNA, ⁇ -actin or HPRT1 mRNA (housekeeping genes) utilizing the relative CT method according to the best practices proposed in Nature Protocols (Schmittgen, T.D. & Livak, K.J. Analyzing real-time PCR data by the comparative C(T) method.
  • mice were allowed to acclimatize for at least three days following their arrival from Jackson Laboratories. The day of study initiation, the mice were weighed and anesthetized with injectable anesthesia, 100 mg/kg ketamine and 5 mg/kg xylazine via intraperitoneal injection. Deep anesthesia was confirmed via toe pinch. One or both eyes were injected intravitreally under a dissecting scope with up to 1 uL of the compound of interest using a Hamilton syringe. Following injection, antibiotic (e.g. terramycin) was placed on the eye. The animal was then allowed to recover from anesthesia in the home cage on a water-recirculating heating pad.
  • injectable anesthesia 100 mg/kg ketamine and 5 mg/kg xylazine via intraperitoneal injection. Deep anesthesia was confirmed via toe pinch.
  • One or both eyes were injected intravitreally under a dissecting scope with up to 1 uL of the compound of interest using a Hamilton syringe. Following injection, antibiotic (e
  • RNALater was removed and the tissue washed twice in PBS. Trizol was then added and RNA isolated using the RNeasy 96 kit via the manufacturer’s instructions.
  • rd10 mice In order to prevent retinal degeneration, rd10 mice are born and reared in the dark. The intravitreal injection of compound of interest or control was performed at 30 days of age under red light conditions to prevent retinal damage. The compound of interest was dosed in the left eye and the vehicle (PBS) control in the right. The mice remained in the dark for 5 days and were then euthanized. The eyes were removed, and the retinas were dissected and prepared for RNA isolation. The regions of interest were placed in RNALater immediately following dissection.24 hours later, the tissue in RNALater was flash frozen and stored at -80°C until RNA isolation.
  • PBS vehicle
  • RNALater Prior to RNA isolation and following thawing, the RNALater was removed and the tissue washed twice in PBS. Trizol was then added and RNA isolated using the RNeasy 96 kit via manufacturer’s instructions. Efficacy Studies in rd10 mice. In order to prevent retinal degeneration, rd10 mice are born and reared in the dark. The intravitreal injection of the oligonucleotide was performed as described herein at 30 days of age under red light conditions to prevent retinal damage. The compound of interest was dosed in the left eye and the vehicle (PBS) control in the right. The mice remained in the dark for 6 days and then were moved into normal light for 4 hours a day.
  • PBS vehicle
  • mice After 9 days of 4-hour per day light exposure, the mice were moved to the dark for overnight dark adaptation. Following dark adaptation, functional assessment of the retina using electroretinography (ERG) was performed as described herein. Following euthanasia, the eyes were removed and placed in 10% neutral buffered formalin for histology. Functional Assessment of Retina using Electroretinography (ERG). Retinal function was assessed in mice following intravitreal injection of compound of interest or vehicle control (PBS). Animals were dark adapted overnight before testing. The day of study initiation, the mice were anesthetized with injectable anesthesia, 100 mg/kg ketamine and 5 mg/kg xylazine via intraperitoneal injection. Deep anesthesia was confirmed via toe pinch.
  • injectable anesthesia 100 mg/kg ketamine and 5 mg/kg xylazine via intraperitoneal injection. Deep anesthesia was confirmed via toe pinch.
  • ERG measurements were performed immediately with a Diagnosys Celeris rodent ERG device (Diagnosys, Lowell, MA).
  • a mouse was placed on a heating pad at 37°C, and its pupils were moistened with 2.5% hypromellose eye lubricant (HUB Pharmaceuticals, Collinso Cucamonga, CA).
  • Light stimulation was produced by an in-house scripted stimulation series in Espion V6 software (Diagnosys, Lowell, MA).
  • Electroretinography was performed using a fully-integrated Celeris system (Diagnosys, Lowell, MA).
  • scotopic (dark-adapted) ERGs were elicited at intensities of 1 cd ⁇ s/m 2 (inter-stimulus interval 20s, 3 repetitions averaged), 40 cd ⁇ s/m 2 (inter-stimulus interval 20s, 3 repetitions averaged).
  • scotopic (dark-adapted) ERGs were elicited at intensities of 0.01 cd ⁇ s/m 2 (inter-stimulus interval 20s, 3 repetitions averaged), 0.1 cd ⁇ s/m 2 (inter-stimulus interval 20s, 3 repetitions averaged), and 1 cd ⁇ s/m 2 (inter-stimulus interval 20s, 3 repetitions averaged).
  • Eyes were then exposed to a white background light (6500 K) at 9 cd/m 2 for ten minutes.
  • Photopic (light-adapted) ERGS were elicited at intensities of 3 cd ⁇ s/m 2 (ISI 2s, 3 repetitions averaged), 10 cd ⁇ s/m 2 (ISI 2s, 3 repetitions averaged), and 3 cd ⁇ s/m 2 flickering at 9.9 Hz (20 repetitions averaged).
  • the ERG signal was acquired at 2 kHz and filtered with a low frequency cutoff at 0.125 Hz and a high frequency cutoff at 300 Hz.
  • Espion software automatically detected the ERG a-waves (first negative ERG component) and b-waves (first positive ERG component). Histology.
  • mice were harvested and placed into 10% neutral buffered formalin (NBF) for 24 hours of fixation before standard tissue processing. Each eye was precisely sectioned to the midline where the optic nerve enters the retina. This gave consistency across all eyes within the study. Sections were dried overnight at 37 o C before hematoxylin & eosin (H&E) staining was performed on the eye sections. This was achieved by dewaxing, dehydrating the sections in tap water, and immersing the sections in hematoxylin reagent for 5 mins. The sections were then washed in running tap water for two minutes before differentiation and bluing.
  • NNF neutral buffered formalin
  • the eosin staining was accomplished by immersing the sections into the eosin reagent for one minute before differentiations in 95% and 100% alcohols prior to placing a coverslip in xylene on the section, in preparation for microscopic examination.
  • Target Engagement Studies in African Green Monkeys A non-GLP study was conducted in African green monkeys at the Virscio/St. Kitts Biomedical Research Foundation facility. Healthy adult male and female animals were selected for inclusion in the study following a baseline screening to assess general and ocular health.
  • Intravitreal injection was performed in both eyes on Day 0 of the study, using a 31-gauge, 0.375 inch needle inserted inferotemporally at the level of the ora serrata ⁇ 2.5 mm posterior to the limbus. Each eye was examined within 30 minutes to 1 hour of injection by slit lamp biomicroscopy following completion of each IVT injection and observations documented.
  • a topical triple antibiotic neomycin, polymyxin, bacitracin ophthalmic ointment (or equivalent) was administered after the examination. If necessary based on examination at one (Day 1) and three days (Day 3) following IVT injection, a steroid was administered subconjunctivally. Intraocular pressure (IOP) measurements were obtained via tonometry at Day 1, Day 3, and Day 13. On Day 0, Day 1, Day 3, and Day 13, eyes were examined by slit lamp biomicroscopy to evaluate ocular health. Serum was collected via the femoral vein just prior to and four hours after IVT injection (Day 0), and on Day 1 and Day 14.
  • IOP Intraocular pressure
  • aqueous humor 50 ⁇ L will be sampled in both eyes with a 0.3 mL insulin syringe with a 31-gauge needle, transferred to cryotubes and stored -70 o C. Eyes were sutured, enucleated and excess orbital tissue was trimmed.
  • the iris/ciliary body of each eye was subdissected; one half was transferred to a cryotube, flash frozen and stored below -70 o C and the other half was transferred to a cryotube containing 200 ⁇ L of RNAlater and stored at 4 o C overnight, after which excess RNA later was removed and the sample was stored below -70 o C.
  • the remainder of the anterior segment was divided in half, with one half flash frozen for storage below -70 o C and the other half transferred to a cryotube containing 200 ⁇ L of RNAlater and stored at 4 o C overnight, after which excess RNAlater was removed and the sample was stored below -70 o C.
  • the vitreous was collected from the posterior eyecup with a syringe, transferred to cryotubes (2 aliquots of ⁇ 1 mL each), flash frozen then stored below -70 o C.
  • longitudinal cuts were made in the eyecup to allow flat mounting, and the flat mount bisected in the plane intersecting the optic nerve and fovea.
  • the flat mount was transferred to a dissection dish containing RNAlater.
  • a 5 mm diameter punch of neural retina/RPE/choroid centered on the fovea was collected from each sample.
  • Two 5 mm diameter punches were collected from each of the cone dense regions in the superior and inferior peripheries outside of the vascular arcade, nasal to the optic nerve, and temporal to the macula.
  • a 3 mm diameter hemi-punch of the optic nerve head was also obtained.
  • the neural retina was separated from the RPE/choroid and each separate tissue was transferred to labeled pre-tared cryotubes containing 200 ⁇ L of RNAlater, weighed and stored at 4 o C overnight, after which excess RNAlater was removed, and the sample was stored below -70 o C. Remaining eye tissue from the retina and choroid was placed in a cryotube and stored below -70 o C.
  • Example 3 Identification and activity of siRNAs targeting mouse NRL Several siRNAs targeting mouse NRL were designed and are shown in Table A. Compounds DT-000126 to DT-000133 are targeted to mouse NRL.
  • Compound DT-000112 is targeted to both mouse and human NRL.
  • the sense and antisense strands of the compounds in Table A were prepared with sugar moiety and internucleotide linkage modifications to increase hybridization affinity, minimize degradation by nucleases, and enhance loading into RISC.
  • nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoronucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides; nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the final two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; all other internucleotide are phosphodiester internucleotide linkages.
  • a hydroxyl group is present at the 5’ carbon of the 3’ terminal nucleotide and the 3’ carbon of the 3’ terminal nucleotide.
  • nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methylnucleotides;
  • nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides;
  • nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the final two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; all other internucleotide are phosphodiester internucleotide linkages.
  • siRNAs Targeting mouse NRL HEK cells were engineered to express mouse neural retina leucine zipper (NRL) for the purpose of identifying siRNAs that inhibit the expression of NRL and are suitable for in vivo characterization.
  • the HEK-NRL cells were than transfected with siRNAs at doses ranging from 3 to 100 nM. RNA was then isolated 48 hours later, reverse transcribed to cDNA and NRL expression was quantified by qPCR. The average NRL expression for each of four replicates was calculated and shown in Table B.
  • siRNAs targeted to mouse NRL inhibited NRL expression in a dose-dependent manner.
  • Table B Screen of Mouse siRNAs in HEK Cells Expressing Mouse NRL
  • Example 4 In Vivo Activity of siRNAs targeting mouse NRL in wild-type mice
  • LCFA long chain fatty acid
  • Conjugated compounds were formed as in the structures below, where the nucleotide shown is the 3’ terminal nucleotide, “B” is nucleobase and “R” is the substituent at the 2’ carbon of the nucleoside sugar.
  • the uptake motif DTx-01-08 was conjugated to the sense strand, using the “C7OH” linker attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand via the phosphate group to form the conjugate group named “C7OH- [DTx-01-08].
  • the uptake motif DTx-01-32 was conjugated to the sense strand, using the “C7OH” linker attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand via the phosphate group to form the conjugate group named “C7OH- [DTx-01-32].
  • the conjugated compounds are shown in Table C. Nucleotide modifications are as indicated above.
  • Table C LCFA-Conjugated siRNAs targeting mouse NRL Compounds conjugated to DTx-01-08 were tested for their ability to inhibit the expression of NRL in the eye of wild-type mice.10 ug of each of DT-000239 to DT-000243 was injected via intravitreal injection into each eye of wildtype mice.
  • Table D In Vivo Activity of Conjugated mouse NRL siRNA DT-000239 suppressed NRL expression to the greatest degree and thus, was further evaluated in in vivo dose-response studies. To compare different LCFA motifs, also tested was DT-000244, which has the same sense strand and antisense strand as DT-00239, but the sense strand is conjugated to DTx-01-32 rather than DTx-01-08.
  • mice DT-000239 and DT-000244 were tested for their ability to reduce the expression of NRL in wild-type mice.
  • C57BL/6J mice at five to six weeks of age received an intravitreal (IVT) injection of 1 ug, 3 ug, or 10 ug of DT-000239 or DT-000244.
  • Vehicle (PBS) and a conjugated siRNA targeting PTEN (DT-000137) were used as control treatments.
  • IVT injection Seven days following IVT injection, the mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The level of mouse NRL mRNA was measured by quantitative real-time PCR.
  • mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation.
  • the level of mouse NRL mRNA was measured by quantitative real-time PCR. The average percentage expression from eight eyes for each treatment at each timepoint was calculated and is shown in Table F.
  • a single injection of DT-000239 resulted in repressed NRL expression out to 28 days.
  • the duration of action is at least 28 days.
  • Table F Duration of Action Following IVT Injection of Conjugated siRNAs As the suppression of NRL also alters the expression of a subset of rod and cone genes, certain rod and cone genes were also selected for measurement of mRNA levels in juvenile mice.
  • mice at 14 days of age received an IVT injection of 10 ug of DT-000239 in the right eye, and PBS in the left eye.
  • the PTEN-targeting siRNA DT-000137 was used as a control compound, with DT-000137 injected in the right eye and PBS injected in the left eye.
  • the mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation.
  • the level of PTEN, NRL, NR2E3, GNB3, REEP6, AAR3, and GNAT1 mRNA was measured by quantitative real-time PCR. The average percentage expression from nine replicates for each treatment was calculated and is shown in Table G.
  • mice C57BL/6J mice at 35 days of age received an IVT injection of 10 ug of DT-000239 in the right eye, and PBS in the left eye. At 42 days of age and 14 days after injection, the mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation.
  • the level of NRL, NR2E3, GNB3, REEP6, ARR3, and GNAT1 mRNA was measured by quantitative real-time PCR. The average percentage expression from eight eyes for each treatment was calculated and is shown in Table H. Similar to the observation in juvenile mice, inhibition of NRL also resulted in decreases in the expression of the rod genes REEP6, NR2E3, and GNAT1, and increases in the expression of the cone genes ARR3 and GNB3.
  • RP retinitis pigmentosa
  • Raising rd10 mice in total darkness has been reported to delay retinal degeneration (Chang et al., 2007, Vision Res., 47(5): 624–633).
  • the effects of inhibiting NRL were evaluated in rd10 mice.
  • rd10 mice were born and reared in the dark.
  • 10 ug of DT-000239 was injected into the right eye and PBS was injected into the left eye.
  • the mice remained in the dark until 31 days of age, at which time the mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation.
  • the level of NRL was measured by quantitative real-time PCR. The average percentage expression from seven eyes for each treatment was calculated.
  • mice After 11 days of 4-hour light exposure (i.e., at day 44), the mice were moved to the dark for overnight dark adaptation. Following dark adaptation, functional assessment of the retina using electroretinography (ERG) was performed. Following euthanasia, the eyes were removed and processed for histological analysis. Hematoxylin & eosin staining was used to visualize photoreceptor cells. ERG results are shown in Table I. Scotopic wave measurements that target rod-pathway function are made from the dark-adapted eye, whereas photopic wave measurement that target cone-pathway function are made from the light-adapted eye. The data illustrate that inhibition of NRL protected photoreceptor function. Histological analysis of retina sections revealed a dramatic preservation of the photoreceptor layer following inhibition of NRL.
  • FIG.1A and 1B Representative images of H&E staining of DT-000239 and PBS-treated retinas from an individual animal are shown in FIG.1A and 1B.
  • Table I Preservation of Photoreceptor Function Following Inhibition of NRL in rd10 mice
  • Example 6 Evaluation of siRNAs targeting NRL in the P23H mouse model of retinitis pigmentosa Compounds provided herein were tested in an experimental mouse model of heterozygous P23H retinitis pigmentosa (P23H RP mice).
  • P23H RP mice carry a point mutation in the rhodopsin gene sequence, whereby a cytosine is substituted with adenine, resulting in the normal “CCC” codon encoding proline being replaced with the “CAC” codon encoding histidine.
  • the phenotype of P23H mice recapitulates the retinopathy and progressive retinal degeneration observed in humans with autosomal dominant retinitis pigmentosa caused by the P23H mutation.
  • the P23H RP model was used to study the effects of targeting NRL. As the suppression of NRL also alters the expression of a subset of rod and cone genes, certain rod and cone genes were also selected for measurement of mRNA levels.
  • P23H RP mice at 14 days of age received a single IVT injection of 10 ug of DT-000239 in the right eye, and PBS (vehicle) in the left eye.
  • a control group of P23H RP mice at 14 days of age received an injection of 10 ug of DT-000137 which targets PTEN.
  • the mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation.
  • the levels of NRL, PTEN, the rod genes NR2E3, REEP6 and GNAT1 and cone genes GNB3 and ARR3 were measured by quantitative real-time PCR. The average percentage expression from eight or nine for each treatment was calculated and is shown in Table J.
  • Retinal function was measured using electroretinography (ERG) at multiple timepoints. Following euthanasia at day 139, the eyes were removed and processed for histological analysis. Hematoxylin & eosin staining was used to visualize photoreceptor cells. Mean ERG results at each time point are shown in Table K and FIG.2A and 2B. Scotopic wave measurements that target rod-pathway function are made from the dark-adapted eye, whereas photopic wave measurement that target cone-pathway function are made from the light-adapted eye. The data illustrate that inhibition of NRL protected photoreceptor function. Table K: Preservation of Photoreceptor Function Following Inhibition of NRL in P23H Retinitis Pigmentosa Mice
  • siRNAs Targeting Mouse and Human NRL To allow for testing of human-targeted siRNAs in mouse experimental models, siRNAs were designed to have an antisense strand that is fully complementary to both the human and mouse NRL mRNAs, i.e. siRNAs that are fully human/mouse cross-reactive. The siRNAs are shown in Table L.
  • Each antisense strand is 21 nucleotides in length and has the modified nucleotide pattern according to Formula I. From the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methylnucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides; nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the final two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; all other internucleotide are phosphodiester internucleotide linkages.
  • a phosphate group is present at the 5’ carbon of the 3’ terminal nucleotide and a hydroxyl group is present at the 3’ carbon of the 3’ terminal nucleotide.
  • Each sense strand is 21 nucleotides in length and has the modified nucleotide pattern according to Formula II.
  • nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoronucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides; nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the final two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; all other internucleotide are phosphodiester internucleotide linkages.
  • a hydroxyl group is present at the 5’ carbon of the 3’ terminal nucleotide and the 3’ carbon of the 3’ terminal nucleotide.
  • Modified sugar moieties are indicated by a subscript notation following the nucleotide, and modified internucleotide linkages are indicated by a superscript notation.
  • a nucleotide followed by the subscript “F” is a 2’-fluoro nucleotide; a nucleotide followed by the subscript “M” is a 2’-O-methyl nucleotide; and a nucleotide without a subscript is a beta-D-deoxyribonucleotide.
  • a superscript “S” is a phosphorothioate internucleotide linkage; all other internucleotide linkages are phosphodiester internucleotide linkages.
  • U S CM is a 2’-fluorouridine linked to a 2’-O-methylcytidine by a phosphorothioate internucleotide linkage.
  • G M U F is a 2-O-methylguanosine linked to a 2’-fluorouridine by a phosphodiester internucleotide linkage.
  • Conjugated compounds were formed as in the structure below, where the nucleotide shown is the 3’ terminal nucleotide, “B” is nucleobase and “R” is the substituent at the 2’ carbon of the nucleoside sugar.
  • the uptake motif DTx-01-08 was conjugated to the sense strand, using the “C7OH” linker attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand via the phosphate group to form the conjugate group named “C7OH- [DTx-01-08].
  • the compounds are shown in Table N.
  • Table N Conjugated fully human/mouse cross reactive siRNAs targeting NRL Compounds conjugated to DTx-01-08 were tested for their ability to inhibit the expression of NRL in the eye of wild-type mice.10 ug of each compound was injected via intravitreal injection into each eye of wildtype mice at 35 days of age. Vehicle (PBS) and a conjugated siRNA targeting PTEN (DT-000137) were used as control treatments. Seven days following injection, retinas were collected, RNA isolated, reverse transcribed to cDNA and NRL expression quantified by qPCR. The average percent NRL expression from 8 eyes was calculated and is shown in Table O.
  • PBS Vehicle
  • DT-000137 conjugated siRNA targeting PTEN
  • siRNAs were designed with the goal of identifying siRNAs that are suitably potent and efficacious against human NRL while also sufficiently activity against mouse NRL to enable testing in experimental mouse models.
  • the siRNAs are shown in Table P.
  • “Start” and “End” correspond to the 5’ and 3’ nucleotide positions of the 19-nucleotide sequence of the human NRL mRNA (NCBI Accession No. NM_006177.5) to which nucleotides 1 to 19 of the sense strand are identical
  • Each row represents a sense and antisense strand pair of an siRNA.
  • Each antisense strand is 21 nucleotides in length and has the modified nucleotide pattern according to Formula I. From the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methylnucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides; nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the final two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; all other internucleotide are phosphodiester internucleotide linkages.
  • a phosphate group is present at the 5’ carbon of the 3’ terminal nucleotide and a hydroxyl group is present at the 3’ carbon of the 3’ terminal nucleotide.
  • Each sense strand is 21 nucleotides in length and has the modified nucleotide pattern according to Formula II.
  • nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoronucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides; nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the final two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; all other internucleotide are phosphodiester internucleotide linkages.
  • a hydroxyl group is present at the 5’ carbon of the 3’ terminal nucleotide and the 3’ carbon of the 3’ terminal nucleotide.
  • Nucleotide modifications are indicated for each sense strand and antisense strand. Modified sugar moieties are indicated by a subscript notation following the nucleotide, and modified internucleotide linkages are indicated by a superscript notation.
  • a nucleotide followed by the subscript “F” is a 2’-fluoro nucleotide; a nucleotide followed by the subscript “M” is a 2’-O-methyl nucleotide; and a nucleotide without a subscript is a beta-D-deoxyribonucleotide.
  • a superscript “S” is a phosphorothioate internucleotide linkage; all other internucleotide linkages are phosphodiester internucleotide linkages.
  • U S CM is a 2’-fluorouridine linked to a 2’-O-methylcytidine by a phosphorothioate internucleotide linkage.
  • G M U F is a 2-O-methylguanosine linked to a 2’-fluorouridine by a phosphodiester internucleotide linkage.
  • the in vitro screening data revealed siRNAs that were active within regions of the NRL coding region.
  • the boundaries of active regions were selected based on the 5’ and 3’ target sites of siRNAs with at least 50% inhibitory activity. Additional target sites were included even if the siRNA resulted in less than 50% inhibitory activity but overlapped with the target region of one or more active siRNAs. These regions are listed in Table R.
  • Table R siRNA-Active Regions of human NRL coding region
  • Example 9 In Vivo Testing of Human NRL siRNAs Human NRL siRNAs that were active within certain target regions of the NRL mRNA were selected for conjugation to uptake motifs and testing in wild-type mice and the rd10 model of retinitis pigmentosa.
  • siRNAs designed to be perfectly complementary to the human NRL mRNA will have sufficient complementarity to the mouse NRL mRNA to inhibit expression of mouse NRL.
  • Conjugated compounds were formed as in the structures below, where the nucleotide shown is the 3’ terminal nucleotide, “B” is nucleobase and “R” is the substituent at the 2’ carbon of the nucleoside sugar.
  • the uptake motif DTx-01-08 was conjugated to the sense strand, using the “C7OH” linker attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand via the phosphate group to form the conjugate group named “C7OH- [DTx-01-08].
  • the uptake motif DTx-01-32 was conjugated to the sense strand, using the “C7OH” linker attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand via the phosphate group to form the conjugate group named “C7OH- [DTx-01-32].
  • the conjugated compounds are shown in Table S. Each conjugated sense strand is 19 nucleotides in length and does not have the 3’ terminal beta-D-deoxythymidine nucleotides present in the corresponding unconjugated sense strand. Nucleotide modifications are indicated as described herein.
  • mice DT-000429, DT-000430, DT-000431, and DT-000432 were tested for their ability to reduce the expression of NRL in wild-type mice.
  • the mouse compound DT-000239 was also tested in this experiment.
  • Vehicle (PBS) was used as a control treatment.
  • C57BL/6J mice at five to six weeks of age received a single intravitreal (IVT) injection of 10 ug of compound, or a single IVT injection of PBS. Seven days following IVT injection, the mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation.
  • IVTT intravitreal
  • mice NRL mRNA The level of mouse NRL mRNA was measured by quantitative real-time PCR. The average percentage expression from 8 eyes was calculated and is shown in Table T.
  • Table T The data illustrate that DT-000239, described above, and each of DT-00429, DT-000430, DT-000431 and DT-000432 reduced NRL expression in the retina seven days following IVT injection.
  • Table T Silencing of NRL Following IVT Injection of Conjugated human NRL siRNAs A time-course experiment was conducted to compare the duration of action of DT-00239, DT-000429, DT-000430, and DT-000432.
  • Vehicle (PBS) was used as a control treatment.
  • the level of NRL mRNA remaining was measured by quantitative real-time PCR.
  • mice at five to six weeks of age received an intravitreal (IVT) injection of 10 ug of DT-000239, DT-000430, or DT-000432.
  • Vehicle (PBS) was used as a control treatment.
  • the level of mouse NRL mRNA was measured by quantitative real-time PCR.
  • NRL inhibition was accompanied by decreases in the expression of the rod genes REEP6, NR2E3, and GNAT1, and increases in the expression of the cone genes ARR3 and GNB3, particularly in the first 28 days after the injection of compound.
  • Table V Duration of Action Following IVT Injection of Conjugated NRL siRNAs
  • RP retinitis pigmentosa
  • mice were born and reared in the dark. At 31 days of age, mice received IVT injections of 1ug, 3ug, or 10 ug of DT-000430 was injected into the left eye, and PBS was injected into the right eye. After five days, mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The level of NRL was measured by quantitative real-time PCR. Also measured was the expression of the rod genes REEP6, NR2E3, and GNAT1, and the cone genes ARR3 and GNB3.
  • Each compound resulted in the dose-dependent suppression of NRL and NRL target genes NR2E3, REEP6, and GNAT1.
  • the expression of the cone gene GNB3 increased in a dose-dependent manner, while the expression of the cone gene ARR3 was not significantly altered.
  • Table W Dose-Dependent Suppression of Genes by Conjugated Human NRL siRNA in rd10 Mice
  • Table X Dose-Dependent Suppression of Genes by Conjugated Human NRL siRNA in rd10 Mice
  • mice After the nine days of light exposure, the mice were moved to the dark for overnight dark adaptation. Following dark adaptation, functional assessment of the retina using electroretinography (ERG) was performed. Following euthanasia, the eyes were removed and processed for histological analysis. Hematoxylin & eosin staining was used to visualize photoreceptor cells. ERG results are shown in Table Y. Scotopic wave measurements that target rod-pathway function are made from the dark-adapted eye, whereas photopic wave measurement that target cone-pathway function are made from the light-adapted eye. The data illustrate that inhibition of NRL protected photoreceptor function.
  • Table Y Preservation of Photoreceptor Function Following Inhibition of NRL in rd10 mice Histological analysis of retina sections from a separate but similarly designed study with DT-000430 and DT-000432 revealed a dramatic preservation of the photoreceptor layer following inhibition of NRL. Representative images of H&E staining of PBS-treated and DT-000430-treated retinas from an individual animal are shown in FIG.5A and 5B. Representative images from PBS-treated and DT-000432-treated retinas from an individual animal are shown in FIG.5C and 5D. In another separate but similarly designed study with DT-000430, H&E staining was performed on retina fixed in Davidson’s fixative—an approach that more optimally preserves retinal structures relative to formalin fixation.
  • FIG.6A and 6B Representative PBS-treated and DT-000430-treated retinas from an individual animal are shown in FIG.6A and 6B. Based on the studies in wild-type and rd10 mice, DT-000430 and DT-000432 were identified as suitable compounds for further optimization. Although the nucleotide sequences of DT-000430 and DT-000432 each contain a mismatch to the mouse NRL mRNA, the data illustrated that the mismatches were tolerated well enough for the compounds to be evaluated in experimental mouse models.
  • Example 10 Optimization of NRL siRNAs To determine whether variations in siRNA nucleotide sequence and/or modified nucleotide pattern would yield compounds with improved properties such as potency and duration of action, further compounds targeting NRL were designed and tested.
  • DT-000726, DT-000727, and DT-000734 are derived from DT-000430 and vary in the length of each strand and chemical modifications.
  • DT-000776, DT-000777, and DT-000778 are conjugated versions of DT-000726, DT-000727, and DT-000734, respectively.
  • DT-000782, DT-000783, and DT-000784 are derived from DT-000432 and vary in the length of each strand and chemical modifications.
  • DT-000785, DT-000786, and DT-000787 are conjugated versions of DT-000782, DT-000783, and DT-000784, respectively.
  • Compounds DT-000735, DT-000736, DT-000737, DT-000738, DT-000828, DT-000829, DT-000830, DT-000831, and DT-000832 are conjugated versions of siRNAs shown in Table P. Nucleotide modifications, uptake motifs and linkers are indicated as described herein.
  • Example 11 Comparison of siRNA Designs in wild-type mice Compounds DT-000776, DT-000777, and DT-000778 (chemical modification and length variants of DT-000430) were tested for their ability to reduce the expression of NRL in wild-type mice, and compared to the activity of compounds DT-000430 and DT-000432.
  • Vehicle (PBS) was used as a control treatment.
  • C57Bl/6J mice at five to six weeks of age received a single intravitreal (IVT) injection of 3 ug or 10 ug of compound, or a single IVT injection of PBS, in each eye.
  • IVTT intravitreal
  • mice Seven days following the IVT injection, mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation.
  • C57Bl/6J mice at five to six weeks of age received a single IVT injection of 10 ug of compound or PBS in each eye.
  • mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation.
  • the level of mouse NRL mRNA was measured by quantitative real-time PCR. The average percentage expression from eight eyes (four mice per treatment) was calculated and is shown in Tables BB (7 days) and CC (28 days).
  • Table BB Silencing of NRL Seven Days Following IVT Injection of Conjugated Human NRL siRNAs
  • Table CC Silencing of NRL 28 Days Following IVT Injection of Conjugated Human NRL siRNAs
  • Compounds DT-000785, DT-000786, and DT-000787 were tested for their ability to reduce the expression of NRL in wild-type mice and compared to the activity of compounds DT-000430 and DT-000432.
  • Vehicle (PBS) was used as a control treatment.
  • C57Bl/6J mice at five to six weeks of age received a single intravitreal (IVT) injection of 3 ug or 10 ug of compound, or a single IVT injection of PBS, in each eye.
  • IVT intravitreal
  • mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation.
  • C57Bl/6J mice at five to six weeks of age received a single IVT injection of 10 ug of compound or PBS in each eye.
  • mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation.
  • mice NRL mRNA The level of mouse NRL mRNA was measured by quantitative real-time PCR. The average percentage expression from eight eyes (four mice per treatment) was calculated and is shown in Tables DD (7 days) and EE (28 days). In this experiment, DT-000432 appeared more potent than DT-000785, DT-000786, and DT-000787. Comparison of the 10 ug dose data at 7 days and 28 days reveals a similar duration of action for DT-00432 and its derivative compounds DT-000785, DT-000786, and DT-000787.
  • Table DD Silencing of NRL Seven Days Following IVT Injection of Conjugated Human NRL siRNAs
  • Table EE Silencing of NRL 28 Days Following IVT Injection of Conjugated Human NRL siRNAs
  • Compounds DT-000735 and DT-000736 target regions of NRL that overlap with the target region of DT-000430.
  • Compounds DT-000737 and DT-000738 target regions of the NRL mRNA that overlap with the target region of DT-000432. These compounds were tested for their ability to reduce the expression of NRL in wild-type mice and compared to the activity of compounds DT-000430 and DT-000432.
  • Vehicle (PBS) was used as a control treatment.
  • IVT intravitreal
  • the average percentage expression from eight eyes (four mice per treatment) was calculated and is shown in Table FF.
  • mice were genetically modified to replace one endogenous mouse NRL allele with a human NRL sequence, so that the mice express one mouse NRL mRNA and one human NRL mRNA.
  • the genetic engineering was performed by the Genetic Engineering Technologies group at The Jackson Laboratory. Briefly, the CRISPR/Cas9 genome editing technology was employed to excise the mouse genomic Nrl (from codon 2 to the stop codon) and insert the human genomic NRL (from codon 2 to the stop codon) at the mouse Nrl start codon.
  • NRL genes of animals from the N1 generation were analyzed by gene sequencing to identify individual animals with one mouse NRL allele and one correctly inserted human NRL allele, or “humanized NRL mice.” These animals were then used to evaluate the activity of NRL-targeting siRNA compounds.
  • Compounds DT-000430, DT-000432, and DT-000776 are cross-reactive with both mouse and human NRL mRNA.
  • Compounds DT-000828, DT-000829, DT-000830, DT-000831, and DT-000832 are specific to the human NRL mRNA. Each of these compounds was tested in the humanized NRL mouse model. Vehicle (PBS) was used as a control treatment. Humanized NRL mice at five to six weeks of age received a single intravitreal (IVT) injection of 3 ug or 10 ug of compound, or a single IVT injection of PBS, in each eye. At seven days following IVT injection, mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The levels of both mouse and human NRL mRNAs was measured by quantitative real-time PCR.
  • IVTT intravitreal
  • Compounds DT-001373, DT-001374, and DT-001375 are specific to the human NRL mRNA. The duration of action of each of these compounds was tested in the humanized NRL mouse model described herein. Vehicle (PBS) was used as a control treatment, and DT- 000776 was used as a comparator treatment. Groups of humanized NRL mice at five to six weeks of age received a single intravitreal (IVT) injection of 10 ug of compound, or a single IVT injection of PBS, in each eye. At 30 days, 60 days, 90 days and 189 days following IVT injection, groups of mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation.
  • IVTT intravitreal
  • the level of human NRL mRNA was measured by quantitative real-time PCR. The average percentage expression from eight eyes (four mice per treatment) was calculated and is shown in Table HH. As shown in Table HH, each compound tested was efficacious in reducing the human NRL mRNA.
  • Table HH Reduction of NRL mRNA in Humanized NRL Mice Following IVT Injection of Conjugated Human NRL siRNAs Compound DT-001386 is specific to the human NRL mRNA and was tested in the humanized NRL mouse model described herein. Vehicle (PBS) was used as a control treatment, and DT-000776 was used as a comparator treatment.
  • mice at five to six weeks of age received a single intravitreal (IVT) injection of 0.3 ug compound, 1 ug compound, or 3 ug of compound, or a single IVT injection of PBS, in each eye.
  • IVT intravitreal
  • mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation.
  • the level of human NRL mRNA was measured by quantitative real-time PCR. The average percentage expression from eight eyes (four mice per treatment) was calculated and is shown in Table II. Both compounds were efficacious in reducing the human NRL mRNA in a dose-responsive manner.
  • ERG results are shown in Table JJ. Scotopic wave measurements that target rod-pathway function were made from the dark-adapted eye, whereas photopic wave measurement that target cone-pathway function were made from the light-adapted eye. The data illustrate that inhibition of NRL protected photoreceptor function in rd10 mice. Additionally, histological analysis of retina sections revealed a dramatic preservation of the photoreceptor layer following inhibition of NRL. Table JJ: Therapeutic Benefit of DT-000776 and DT-000430 in rd10 mice Each of compounds DT-000430, DT-000432, and DT-000776 was additionally tested in the P23H mouse model of retinitis pigmentosa.
  • Example 14 Evaluation of Human NRL siRNAs in Non-Human Primates A non-GLP study was conducted in African green monkeys to evaluate the ocular distribution, pharmacodynamics, and tolerance of NRL siRNAs in non-human primates. Compounds DT-000432 and DT-000776 were selected for evaluation.
  • PBS vehicle
  • a total of 12 animals were randomized into groups of two for treatment as follows: PBS, 75 ⁇ g DT-000432, 300 ⁇ g DT-000432, 18.75 ⁇ g DT-000776, 75 ⁇ g DT-000776, and 300 ⁇ g DT-000776.
  • PBS or compound was administered by intravitreal injection (IVT) on Day 0 of the study.
  • IVT intravitreal injection
  • animals were euthanized, the eyes were enucleated, and 5 mm biopsy punches of tissue were collected from various regions of the eye. Each biopsy sample was prepared for RNA isolation.
  • the level of NRL mRNA was measured by quantitative real-time PCR.

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Abstract

Provided herein, inter alia, are compounds for inhibiting neural retina leucine zipper (NRL) mRNA. Also provided herein are methods of using such compounds for the treatment of retinitis pigmentosa.

Description

COMPOUNDS TARGETING NRL FOR THE TREATMENT OF RETINITIS PIGMENTOSA CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of US Provisional Application No.63/246,763 filed September 21, 2021, the contents of which is hereby incorporated herein in its entirety and for all purposes. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING The contents of the electronic sequence listing (052974- 506001WO_Sequence_Listing_ST26.xml; Size: 515,841 bytes; and Date of Creation: September 20, 2022) is hereby incorporated by reference in its entirety. FIELD The present disclosure relates to compounds and methods for the treatment of retinitis pigmentosa. More specifically, the present disclosure relates, inter alia, to inhibitors of neural retina leucine zipper (NRL) and their use in the treatment of retinitis pigmentosa. BACKGROUND Retinitis pigmentosa (RP) is a hereditary retinal degenerative disease characterized by the loss of photoreceptors, leading to severe visual impairment and eventually complete blindness. Photoreceptors are specialized neuronal cells in the retina that capture light and convert it to electrical signals in the process known as phototransduction. The two types of photoreceptors are rods and cones. Rods are stimulated by dim light and responsible for vision in dark conditions. Cones are stimulated by bright light and responsible for color vision and vision in light conditions. RP typically involves degeneration of rods, followed by a loss of cones. Thus, in the primary stage RP typically presents with night blindness (nyctalopia). In the advanced stage, subjects with RP experience visual impairment under light conditions, in addition to the loss of peripheral and central vision. RP has been linked to over 3,000 mutations in approximately 60 genes, most of which are critical for rod development and function (Hartong et al., 2006). These mutations may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Neural retina leucine zipper (NRL) is a rod-specific transcription factor that is one of several transcription factors responsible for the regulation of photoreceptor gene expression. In experimental models of RP, disruption of NRL expression by genetic manipulation has shown that NRL is necessary for normal levels of gene expression in mature rods. Further, the resultant reduction in rod gene expression was sufficient to promote the survival of photoreceptors and restore visual function in experimental models of RP (Montana et al., 2013, PNAS 110: 1732–1737; Zhu et al., 2017, Cell Research 27: 830–833; Yu et al., 2017, Nature Communications 8: 14716). While efforts are underway to identify therapeutic interventions that prevent or slow vision loss associated with RP, there is a need for therapies that address the fundamental cause of RP: photoreceptor degeneration. As the disruption of NRL provides protects photoreceptors in experimental models of RP, the inhibition of NRL with nucleic acid therapeutics is a promising therapeutic approach for the treatment of RP. Disclosed herein, inter alia, are solutions to these and other problems in the art. SUMMARY Provided herein are, inter alia, nucleic acid compounds targeted to the NRL mRNA. In embodiments, provided is a compound comprising an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein each of the antisense strand and sense strands is 15 to 25 nucleotides in length, the nucleotide sequence of the antisense strand is at least 90% complementary to the nucleotide sequence of the NRL mRNA (SEQ ID NO: 1), and the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 contiguous nucleotides of any one of nucleotides 501 to 563 of SEQ ID NO: 1, nucleotides 602 to 626 of SEQ ID NO: 1, nucleotides 623 to 654 of SEQ ID NO: 1, nucleotides 684 to 710 of SEQ ID NO: 1, nucleotides 741 to 765 of SEQ ID NO: 1, nucleotides 759 to 777 of SEQ ID NO: 1, nucleotides 882 to 909 of SEQ ID NO: 1, or nucleotides 1111 to 1133 of SEQ ID NO: 1, and the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand. In embodiments, the antisense strand and the sense strand are not covalently linked. In embodiments, at least one nucleotide of the antisense strand is a modified nucleotide. In embodiments, at least one nucleotide of the sense strand is a modified nucleotide. In embodiments, the antisense strand is 21 to 23 nucleotides in length. In embodiments, the sense strand is 21 to 23 nucleotides in length. In embodiments, the hybridization of the antisense strand to the sense strand forms at least one blunt end. In embodiments, at least one strand comprises a 3’ nucleotide overhand of one to five nucleotides. In embodiments, the compound comprises a ligand covalently linked to the antisense strand or the sense strand. In embodiments, the compound has the structure: A is the sense strand or the antisense strand. t is an integer from 1 to 5. L3 and L4 are independently a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, -C(O)N(R24)-, -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O-P(S)(NR23R24)-N-, -O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene. Each R23, R24 and R25 is independently hydrogen or unsubstituted C1-C10 alkyl. L5 is -L5A-L5B-L5C-L5D-L5E-. L6 is -L6A-L6B-L6C-L6D-L6E-. L5A, L5B, L5C, L5D, L5E, L6A, L6B, L6C, L6D, and L6E are independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, –C(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; and each R23, R24 and R25 is independently hydrogen or unsubstituted C1-C10 alkyl. R1 and R2 are independently unsubstituted C1-C25 alkyl, wherein at least one of R1 and R2 is unsubstituted C9-C19 alkyl. R3 is hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, –N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, the compound is selected from DT-000429, DT-000430, DT- 000431, DT-000432, DT-000735, DT-000736, DT-000737, DT-000738, DT-000776, DT- 000777, DT-000778, DT-000785, DT-000786, DT-000787, DT-000828, DT-000829, DT- 000830, DT-000831, and DT-000832. In embodiments, the compound is selected from DT- 001373, DT-001374, DT-001375, and DT-001386. In embodiments, provided herein is a pharmaceutical composition comprising the compound as described herein. In embodiments, provided is a method of inhibiting the expression of neural retina leucine zipper (NRL) mRNA in a cell, comprising contacting the cell with the compound as described herein. In embodiments, provided is a method of inhibiting the expression of neural retina leucine zipper (NRL) in a subject, comprising administering to the subject an effective amount the compound or pharmaceutical composition as described herein. In embodiments, provided is a method of treating retinitis pigmentosa, comprising administering to a subject in need thereof an effective amount of the compound or pharmaceutical composition as described herein. In embodiments, provided is the compound, or pharmaceutical composition comprising the compound as described herein, for use in therapy. In embodiments, provided is the compound, or pharmaceutical composition comprising the compound as described herein, for use in the treatment of retinitis pigmentosa. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1A shows a representative image of H&E staining of the photoreceptor layer in the retina of a PBS-treated rd10 mouse. FIG.1B shows a representative image of H&E staining of the photoreceptor layer in the retina of a DT-000239-treated rd10 mouse. FIG.2A shows the scotopic wave measurements over time in the eyes of P23H RP mice following administration of PBS in the left eye and DT-000239 in the right eye. FIG.2B shows the photopic wave measurements over time in the eyes of P23H RP mice following administration of PBS in the left eye and DT-000239 in the right eye. FIG.3A shows a representative image of H&E staining of the photoreceptor layer in the retina of a PBS-treated P23H RP mouse. FIG.3B shows a representative image of H&E staining of the photoreceptor layer in the retina of a DT-000239-treated P23H RP mouse. FIG.4 shows the average percent NRL mRNA level over time following IVT injection of PBS, DT-000239, DT-000430, or DT-000432. FIG.5A shows a representative image of H&E staining of the photoreceptor layer in the retina of a PBS-treated rd10 mouse. FIG.5B shows a representative image of H&E staining of the photoreceptor layer in the retina of a DT-000430-treated rd10 mouse. FIG.5C shows a representative image of H&E staining of the photoreceptor layer in the retina of a PBS-treated rd10 mouse. FIG.5D shows a representative image of H&E staining of the photoreceptor layer in the retina of a DT-000432-treated rd10 mouse. FIG.6A shows a representative image of H&E staining of the photoreceptor layer in the retina of a PBS-treated rd10 mouse. FIG.6B shows a representative image of H&E staining of the photoreceptor layer in the retina of a DT-000430-treated rd10 mouse. FIG.7A shows the amount of human NRL mRNA remaining following IVT injection of PBS or compound in humanized NRL mice. FIG.7B shows the amount of mouse NRL mRNA remaining following IVT injection of PBS or compound in humanized NRL mice. DETAILED DESCRIPTION Overview Retinitis pigmentosa (RP) is a hereditary retinal degenerative disease characterized by the loss of photoreceptors. In experimental models of RP, disruption of rod-specific transcription factor NRL by genetic manipulation provides a protective effect to photoreceptors. These reports are promising, however, there remains a need for strategies other than gene therapy to target NRL and protect against RP. Embodiments of the present disclosure relate to nucleic acid compounds for inhibiting the expression of NRL, and their use for the treatment of RP. Definitions Unless defined otherwise, all technical terms, scientific terms, abbreviations, chemical structures, and chemical formulae used herein have the same meaning as is commonly understood by one of ordinary skill in the art. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are employed. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. As used in this specification, whether in a transitional phrase or in the body of the claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least.” When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term “comprising” means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components. Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-. “Retinitis pigmentosa” or “RP” means an inherited disease characterized by loss of photoreceptor function and eventual blindness. RP is caused by a mutation in one of various genes encoding proteins that participate in the visual cycle. Mutations that cause RP may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. “Compound” means a molecule comprising linked monomeric nucleotides. A compound may have one or more modified nucleotides. In embodiments, a compound comprises a double-stranded nucleic acid. In embodiments, a compound comprises a single-stranded nucleic acid. A compound may be provided as a pharmaceutical salt. A compound may be provided as a pharmaceutical composition. “Oligonucleotide” means a polymer of linked monomeric nucleotides. One or more nucleotides of an oligonucleotide may be a modified nucleotide. “Double-stranded nucleic acid” means a first nucleotide sequence hybridized to a second nucleotide sequence to form a duplex structure. Double-stranded nucleic acids include structures formed from annealing a first oligonucleotide to a second, complementary oligonucleotide, as in an siRNA. Such double-stranded nucleic acids may have a short nucleotide overhang at one or both ends of the duplex structure. Double-stranded nucleic acids also include structures formed from a single oligonucleotide with sufficient length and self-complementarity to form a duplex structure, as in an shRNA. Such double-stranded nucleic acids include stem-loop structures. A double-stranded nucleic acid may include one or more modifications relative to a naturally occurring terminus, sugar, nucleobase, and/or phosphate group. “Double-stranded region” means the portion of a double-stranded nucleic acid where nucleotides of the first nucleotide sequence are hybridized to nucleotides of the second nucleotide sequence. A double-stranded region can be a defined portion within a double-stranded nucleic acid that is shorter than (e.g. encompassed by) the full double-stranded nucleic acid. Alternatively, a double-stranded region can be the same length as the full double-stranded nucleic acid. A double-stranded region may contain one or more mismatches between the first and second nucleotide sequences, and retain the ability hybridize with each other. Double-stranded regions do not include nucleotide overhangs. “Antisense strand” means an oligonucleotide that is complementary to a target RNA (e.g. a mRNA) and is incorporated into the RNA-induced silencing complex (RISC) to direct gene silencing in a sequence-specific manner through the RNA interference pathway. The antisense strand may also be referred to as the “guide strand.” “Sense strand” means an oligonucleotide that is complementary to the antisense strand of a double-stranded nucleic acid. The sense strand is typically degraded following incorporation of the antisense strand into RISC. The sense strand may also be referred to as the “passenger strand.” “Nucleotide overhang” means an extension of one or more unpaired nucleotides from the double-stranded region of a double-stranded nucleic acid. For example, when the 3’ terminus of an antisense strand extends beyond the 5’ terminus of a sense strand, the 3’ terminus of the antisense strand has a nucleotide overhang. A nucleotide overhang can be one, two, three, four or five nucleotides. One or more nucleotides of a nucleotide overhang may be a modified nucleotide. A nucleotide overhang may be on the antisense strand, the sense strand, or both the antisense and sense strands. “Blunt end” means a given terminus of a double-stranded nucleic acid with no unpaired nucleotides extending from the double-stranded region, i.e. there is no nucleotide overhang. A double-stranded nucleic acid may have a blunt end at one or both termini. “siRNA” means a double-stranded nucleic acid formed from separate antisense and sense strands, which directs gene silencing in a sequence-specific manner by facilitating mRNA degradation before translation through the RNA interference pathway. The antisense and sense strands of an siRNA are not covalently linked. “shRNA” means a double-stranded nucleic acid containing a loop structure that is processed in a cell to an siRNA which directs gene silencing in a sequence-specific manner, by facilitating mRNA degradation before translation through the RNA interference pathway. “Single-stranded nucleic acid” means an antisense strand that is not hybridized to a complementary strand. A single-stranded nucleic acid is incorporated into RISC to direct gene silencing in a sequence-specific manner by facilitating mRNA degradation before translation through the RNA interference pathway. “Hybridize” means the annealing of one nucleotide sequence to another nucleotide sequence based at least in part on nucleotide sequence complementarity. In embodiments, an antisense strand is hybridized to a sense strand. In embodiments, an antisense strand hybridizes to a target mRNA sequence. “Complementary” means nucleobases having the capacity to pair non-covalently via hydrogen bonding. “Fully complementary” means each nucleobase of a first nucleotide sequence is complementary to each nucleobase of a second nucleotide sequence. In embodiments, an antisense strand is fully complementary to its target mRNA. In embodiments, a sense strand and an antisense strand of double-stranded nucleic acid are fully complementary over their entire lengths. In embodiments, a sense strand and an antisense strand of double-stranded nucleic acid are fully complementary over the entire length of the double-stranded region of the siRNA, and one or both termini of either strand comprises single-stranded nucleotides. "Identical" in the context of nucleotide sequences, means having the same nucleotide sequence, independent of sugar, linkage, and/or nucleobase modifications and independent of the methylation state of any pyrimidines present. "Percent identity" means the number of nucleobases in a first nucleotide sequence that are identical to nucleobases at corresponding positions in a second nucleotide sequence, divided by the total number of nucleobases in the first nucleotide sequence. "Mismatch" means a nucleobase of a first nucleotide sequence that is not capable of Watson-Crick pairing with a nucleobase at a corresponding position of a second nucleotide sequence. “Nucleoside” means a monomer of a nucleobase and a pentofuranosyl sugar (e.g., either ribose or deoxyribose). Nucleosides may comprise bases such as A, C, G, T, or U, or modifications thereof. Nucleosides may be modified at the base and/or and the sugar. In embodiments, a nucleoside is a deoxyribonucleoside. In embodiments, the nucleoside is a ribonucleoside. “Nucleotide” means a nucleoside covalently linked to a phosphate group at the 5’ carbon of the pentafuranosyl sugar. Nucleotides may be modified at one or more of the nucleobase, sugar moiety, internucleotide linkage and/or phosphate group. “Nucleobase” means a heterocyclic base moiety capable of non-covalently pairing. Nucleobases include pyrimidines and purines. Unless stated otherwise, numbering of nucleotide atoms is according to standard numbering convention, with the carbons of the pentafuranosyl sugar numbered 1’ through 5’, and the nucleobase atoms numbered 1 through 9 for purines and 1 through 6 for pyrimidines. “Modified nucleoside” means a nucleoside having one or more modifications relative to a naturally occurring nucleoside. Such alterations may be present in a nucleobase and/or sugar moiety of the nucleoside. A modified nucleoside may have a modified sugar moiety and an unmodified nucleobase. A modified nucleoside may have a modified sugar moiety and a modified nucleobase. “Modified nucleotide” means a nucleotide having one or more alterations relative to a naturally occurring nucleotide. An alteration may be present in an internucleoside linkage, a nucleobase, and/or a sugar moiety of the nucleotide. A modified nucleotide may have a modified sugar moiety and an unmodified phosphate group. A modified nucleotide may have an unmodified sugar moiety and a modified phosphate group. A modified nucleotide may have a modified sugar moiety and an unmodified nucleobase. A modified nucleotide may have a modified sugar moiety and a modified phosphate group. “Modified nucleobase” means a nucleobase having one or more alterations relative to a naturally occurring nucleobase. “Modified phosphate group” means any change from a naturally occurring phosphate group of a nucleotide. “Modified internucleotide linkage” means any change from a naturally occurring phosphodiester linkage between two nucleotides. “Phosphorothioate internucleotide linkage” means a substituted phosphodiester internucleotide linkage where one of the non-bridging atoms is a sulfur atom. “Modified sugar moiety” means a sugar of a nucleotide having any change and/or substitution from a naturally occurring sugar moiety. “beta-D-deoxyribonucleoside” means a naturally occurring nucleoside monomer of DNA. “beta-D-ribonucleoside” means a naturally occurring nucleoside monomer of RNA. “2’-O-methyl sugar” or “2’-OMe sugar” means a sugar having an O-CH3 substitution at the 2’ position of the pentofuranosyl sugar. “2’-O-methoxyethyl sugar” or “2’-MOE sugar” means a sugar having an OCH2CH2OCH3 substitution at the 2’ position of the pentofuranosyl sugar. “2’-fluoro sugar” or “2’-F sugar” means a sugar having a fluoro substitution at the 2’ position of the pentofuranosyl sugar. “Bicyclic sugar” means a modified sugar moiety comprising a linkage connecting the 2’-carbon and 4’-carbon of the pentafuranosyl sugar, resulting in a bicyclic structure. Nonlimiting exemplary bicyclic sugar moieties include LNA, ENA, cEt, S-cEt, and R-cEt. “Locked nucleic acid (LNA) sugar” means a substituted sugar moiety comprising a - CH2-O- linkage between the 4’ and 2’ furanose ring atoms. “ENA sugar” means a substituted sugar moiety comprising a -(CH2)2-O- linkage between the 4’ and 2’ furanose ring atoms. “2’-O-methyl nucleotide” means a nucleotide having an O-methyl substitution at the 2’ position of the pentofuranosyl sugar. A 2’-O-methyl nucleotide may have a further modification in addition to the modified sugar moiety, for example a modified nucleobase and/or phosphate group. “2’-fluoro nucleotide” means a nucleotide having a fluoro substitution at the 2’ position of the pentofuranosyl sugar. A 2’-O-fluoro nucleotide may have a further modification in addition to the modified sugar moiety, for example a modified nucleobase and/or phosphate group. “Bicyclic nucleotide” means a nucleotide having a linkage connecting the 2’-carbon and 4’-carbon of the pentafuranosyl sugar. A bicyclic nucleotide may have a further modification in addition to the modified sugar moiety, for example a modified nucleobase and/or phosphate group. “Pharmaceutical salt” means a salt form of a compound that retains the biological effectiveness and properties of a compound and does not have undesired effects when administered to a subject. “Therapeutically effective amount” means an amount sufficient for a compound to provide a therapeutic benefit to a subject. “Subject” used herein means a human or non-human animal selected for treatment or therapy. In embodiments, a subject is a human. “Administration” means providing a pharmaceutical agent or composition to a subject, and includes administration performed by a medical professional and self-administration. In embodiments, administration is intraocular administration. In embodiments, administration is topical administration. “Treating” or “treatment” means the administration of one or more pharmaceutical agents to a subject to achieve a desired clinical result, including but not limited to the alleviation, amelioration, or slowing of the progression of at least one indicator or symptom of a disease in a subject. “Prevent the onset of” means the prevention of the appearance of at least one indicator or symptom of a disease in a subject at risk for developing the disease. “Effective amount” means an amount sufficient for a compound that, when administered to a subject, is sufficient to effect treatment of a disease in the subject. An effective amount may vary depending on the one or more of the compound, its mode of administration, the severity of the disease in the subject, concomitant pharmaceutical agents the subject is receiving, and characteristics of the subject such as the subject’s medical history, age, and weight. The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkyl moiety may be fully saturated. An alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds. An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds. The term “cycloalkyl” means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In embodiments, cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH2)w, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. In embodiments, the multicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclic cycloalkyl groups include, but are not limited to tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl, and perhydrophenoxazin-1-yl. In embodiments, a cycloalkyl is a cycloalkenyl. The term “cycloalkenyl” is used in accordance with its plain ordinary meaning. In embodiments, a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. In embodiments, monocyclic cycloalkenyl ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon carbon double bond), but not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH2)w, where w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct 2 enyl. In embodiments, fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. In embodiments, the multicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. In embodiments, a heterocycloalkyl is a heterocyclyl. The term “heterocyclyl” as used herein, means a monocyclic, bicyclic, or multicyclic heterocycle. The heterocyclyl monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3 dioxanyl, 1,3 dioxolanyl, 1,3 dithiolanyl, 1,3 dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1 dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The heterocyclyl bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl. The heterocyclyl bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3 dihydrobenzofuran 2 yl, 2,3 dihydrobenzofuran 3 yl, indolin 1 yl, indolin 2 yl, indolin 3 yl, 2,3 dihydrobenzothien 2 yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro 1H indolyl, and octahydrobenzofuranyl. In embodiments, heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia. Multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. The multicyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring. In embodiments, multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclic heterocyclyl groups include, but are not limited to 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl, 9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl. The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. The term “alkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne. In embodiments, the alkylene is fully saturated. In embodiments, the alkylene is monounsaturated. In embodiments, the alkylene is polyunsaturated. An alkenylene includes one or more double bondss. An alkynylene includes one or more triple bonds. The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, S, Si, or P), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds. The term “heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds. In embodiments, the heteroalkyl is fully saturated. In embodiments, the heteroalkyl is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated. Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO2R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like. The term “heteroalkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene. The term “heteroalkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne. In embodiments, the heteroalkylene is fully saturated. In embodiments, the heteroalkylene is monounsaturated. In embodiments, the heteroalkylene is polyunsaturated. A heteroalkenylene includes one or more double bonds. A heteroalkynylene includes one or more triple bonds. The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. In embodiments, the cycloalkyl is fully saturated. In embodiments, the cycloalkyl is monounsaturated. In embodiments, the cycloalkyl is polyunsaturated. In embodiments, the heterocycloalkyl is fully saturated. In embodiments, the heterocycloalkyl is monounsaturated. In embodiments, the heterocycloalkyl is polyunsaturated. The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. The term “acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. In embodiments, a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within an aryl ring of the multiple rings. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). In embodiments, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heteroaromatic ring of the multiple rings). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen. Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g. all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different. The symbol “ ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula. The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. The term “alkylarylene” as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula: . An alkylarylene moiety may be substituted (e.g. with a substituent group) on the alkylene moiety or the arylene linker (e.g. at carbons 2, 3, 4, or 6) with halogen, oxo, -N3, -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3 -SO3H, , -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted. Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below. Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR'', in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like). Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR'', in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R'', R''', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' groups when more than one of these groups is present. Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency. Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure. Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-, wherein T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O) -, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')s-X'- (C''R''R''')d-, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si). A “substituent group,” as used herein, means a group selected from the following moieties: (A) oxo, halogen, –CF3, –CCl3, –CBr3, –CI3, –CHF2, –CHCl2, –CHBr2, –CHI2, -CH2F, –CH2Cl, –CH2Br, –CH2I, -CN, -N3, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SCH3, -SO3H, -SO4H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, –OCF3, –OCCl3, –OCBr3, –OCI3, –OCHF2, –OCHCl2, –OCHBr2, –OCHI2, –OCH2F, –OCH2Cl, –OCH2Br, -OCH2I, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (B) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (i) oxo, halogen, –CF3, –CCl3, –CBr3, –CI3, –CHF2, –CHCl2, –CHBr2, –CHI2, -CH2F, –CH2Cl, –CH2Br, –CH2I, -CN, -N3, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SCH3, -SO3H, -SO4H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, –OCF3, –OCCl3, –OCBr3, –OCI3, –OCHF2, –OCHCl2, –OCHBr2, –OCHI2, –OCH2F, –OCH2Cl, –OCH2Br, -OCH2I, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (ii) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (a) oxo, halogen, –CF3, –CCl3, –CBr3, –CI3, –CHF2, –CHCl2, –CHBr2, –CHI2, -CH2F, –CH2Cl, –CH2Br, –CH2I, -CN, -N3, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SCH3, -SO3H, -SO4H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, –OCF3, –OCCl3, –OCBr3, –OCI3, –OCHF2, –OCHCl2, –OCHBr2, –OCHI2, –OCH2F, –OCH2Cl, –OCH2Br, -OCH2I, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (b) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: oxo, halogen, –CF3, –CCl3, –CBr3, –CI3, –CHF2, –CHCl2, –CHBr2, –CHI2, -CH2F, –CH2Cl, –CH2Br, –CH2I, -CN, -N3, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SCH3, -SO3H, -SO4H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, –OCF3, –OCCl3, –OCBr3, –OCI3, –OCHF2, –OCHCl2, –OCHBr2, –OCHI2, –OCH2F, –OCH2Cl, –OCH2Br, -OCH2I, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). A “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. A “lower substituent” or “ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and/or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene, respectively). In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different. In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different. In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different. In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group is different. In embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 3 to 8 membered heterocycloalkyl, each or unsubstituted aryl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C6-C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 5 to 10 membered heteroaryl. In embodiments herein, each substituted or unsubstituted alkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C6-C10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 5 to 10 membered heteroarylene. In embodiments, each substituted or unsubstituted alkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C6-C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 5 to 9 membered heteroaryl. In embodiments, each substituted or unsubstituted alkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C6-C10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 5 to 9 membered heteroarylene. In embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below. Certain compounds provided herein possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of provided herein do not include those that are known in art to be too unstable to synthesize and/or isolate. Compounds provided herein include those in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms. The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. It will be apparent to one skilled in the art that certain compounds provided herein may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the present disclosure. Where the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the (R) and (S) configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds, generally recognized as stable by those skilled in the art, are within the scope of the present disclosure. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, replacement of fluoride by 18F, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of the present disclosure. The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds provided herein, whether radioactive or not, are inlcuded within the present disclosure. It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit. “Analog,” or “analogue” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound. The terms "a" or "an," as used in herein means one or more. In addition, the phrase "substituted with a[n]," as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is "substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl," the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls. Where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman decimal symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13 substituents are present, each R13 substituent may be distinguished as R13.1, R13.2, R13.3, R13.4, etc., wherein each of R13.1, R13.2, R13.3, R13.4, etc. is defined within the scope of the definition of R13 and optionally differently. The terms "a" or "an," as used in herein means one or more. In addition, the phrase "substituted with a[n]," as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is "substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl," the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls. Description of compounds of provided herein is limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds. Compounds Embodiments of the present disclosure relate to compounds targeted to the human neural retina leucine zipper (NRL) mRNA (NCBI Reference Sequence NM_006177.5, deposited with GenBank on June 2, 2019; SEQ ID NO: 1). The compounds include double-stranded nucleic acids and single-stranded nucleic acids that act through the RNA interference pathway to inhibit the expression of the NRL mRNA. In embodiments, a compound is a double-stranded nucleic acid comprising an antisense strand complementary to the NRL mRNA and a sense strand complementary to the antisense strand. In embodiments, the antisense strand and sense strand of a compound are two separate strands and are not covalently linked and form a small interfering RNA (siRNA). In embodiments, the antisense strand and sense strand of a compound are covalently linked by a nucleotide linker to form a short hairpin RNA (shRNA). In embodiments, the compound is a single-stranded nucleic acid comprising an antisense strand complementary to the NRL mRNA (ssRNAi). Provided herein are compounds for inhibiting the expression of the neural retina leucine zipper (NRL) mRNA, wherein the compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, each of the antisense strand and sense strands is 15 to 25 nucleotides in length, the nucleotide sequence of the antisense strand is at least 90% complementary to the nucleotide sequence of the NRL mRNA (SEQ ID NO: 1), and the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand. Provided herein are compounds for inhibiting the expression of the neural retina leucine zipper (NRL) mRNA, wherein the compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, each of the antisense strand and sense strands is 15 to 25 nucleotides in length, the antisense strand comprises a nucleotide sequence that is at least 90% complementary to at least 15 contiguous nucleotides of any one of nucleotides 501 to 563 of SEQ ID NO: 1, nucleotides 602 to 626 of SEQ ID NO: 1, nucleotides 623 to 654 of SEQ ID NO: 1, nucleotides 741 to 765 of SEQ ID NO: 1, nucleotides 759 to 777 of SEQ ID NO: 1, nucleotides 882 to 909 of SEQ ID NO: 1, or nucleotides 1111 to 1133 of SEQ ID NO: 1, and the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand. Provided herein are compounds for inhibiting the expression of the neural retina leucine zipper (NRL) mRNA, wherein the compound is a single-stranded nucleic acid comprising an antisense strand, wherein the antisense strand is 15 to 25 nucleotides in length and the nucleotide sequence of the antisense strand is at least 90% complementary to the nucleotide sequence of the NRL mRNA (SEQ ID NO: 1). Provided herein are compounds for inhibiting the expression of the neural retina leucine zipper (NRL) mRNA, wherein the compound is a single-stranded nucleic acid comprising an antisense strand, wherein the antisense strand is 15 to 25 nucleotides in length and the antisense strand comprises a nucleotide sequence that is at least 90% complementary to at least 15 contiguous nucleotides of any one of nucleotides 501 to 563 of SEQ ID NO: 1, nucleotides 602 to 626 of SEQ ID NO: 1, nucleotides 623 to 654 of SEQ ID NO: 1, nucleotides 741 to 765 of SEQ ID NO: 1, nucleotides 759 to 777 of SEQ ID NO: 1, nucleotides 882 to 909 of SEQ ID NO: 1, or nucleotides 1111 to 1133 of SEQ ID NO: 1. Certain nucleotide sequences of sense and antisense strands are shown in Table 1. “Start” and “End” correspond to the 5’ and 3’ nucleotide positions of the nucleotide sequence of the human NRL mRNA) to which the nucleotides of the sense strand, excluding any thymine bases, are identical, and the 5’ and 3’ nucleotide positions of the nucleotide sequence of the human NRL mRNA (SEQ ID NO: 1) to which the nucleotides the antisense strand, excluding any thymine bases, are complementary. A double-stranded compound provided herein may comprise any pair of sense strand and antisense strand described in Table 1. A single-stranded nucleic acid may comprise any antisense strand described in Table 1. Table 1: Unmodified Nucleotide Sequences
Provided below are features of compounds, such as length, nucleotide sequence, and nucleotide modifications. It is understood that an embodiment of an antisense strand may apply to the antisense strand of a single-stranded nucleic acid or a double-stranded nucleic acid. Further, it is understood that an embodiment of a sense strand may apply to a sense strand of any double-stranded nucleic acid provided herein, including siRNAs and shRNAs. In embodiments, an antisense strand is 15 to 25 nucleotides in length. In embodiments, an antisense strand is 17 to 23 nucleotides in length. In embodiments, an antisense strand is 19 to 21 nucleotides in length. In embodiments, an antisense strand is 21 to 23 nucleotides in length. In embodiments, an antisense strand is 15 nucleotides in length. In embodiments, an antisense strand is 16 nucleotides in length. In embodiments, an antisense strand is 17 nucleotides in length. In embodiments, an antisense strand is 18 nucleotides in length. In embodiments, an antisense strand is 19 nucleotides in length. In embodiments, an antisense strand is 20 nucleotides in length. In embodiments, an antisense strand is 21 nucleotides in length. In embodiments, an antisense strand is 22 nucleotides in length. In embodiments, an antisense strand is 23 nucleotides in length. In embodiments, an antisense strand is 24 nucleotides in length. In embodiments, an antisense strand is 25 nucleotides in length. In embodiments, a sense strand is 15 to 25 nucleotides in length. In embodiments, a sense strand is 17 to 23 nucleotides in length. In embodiments, a sense strand is 19 to 21 nucleotides in length. In embodiments, a sense strand is 21 to 23 nucleotides in length. In embodiments, a sense strand is 15 nucleotides in length. In embodiments, a sense strand is 16 nucleotides in length. In embodiments, a sense strand is 17 nucleotides in length. In embodiments, a sense strand is 18 nucleotides in length. In embodiments, a sense strand is 19 nucleotides in length. In embodiments, a sense strand is 20 nucleotides in length. In embodiments, a sense strand is 21 nucleotides in length. In embodiments, a sense strand is 22 nucleotides in length. In embodiments, a sense strand is 23 nucleotides in length. In embodiments, a sense strand is 24 nucleotides in length. In embodiments, a sense strand is 25 nucleotides in length. In embodiments, the length of the sense strand is identical to the length of the antisense strand. In embodiments, the length of the sense strand is greater than the length of the antisense strand. In embodiments, the length of the sense strand is less than the length of the antisense strand. The double-stranded region of a double-stranded nucleic acid may be from 15 to 25 nucleobase pairs in length, depending on the lengths of the sense strand and the antisense strand. In embodiments, the double-stranded region is 17 to 23 nucleobase pairs in length. In embodiments, the double-stranded region is 19 to 21 nucleobase pairs in length. In embodiments, the double-stranded region is 21 to 23 nucleotides in length. In embodiments, the double-stranded region is 15 nucleobase pairs in length. In embodiments, the double-stranded region is 16 nucleobase pairs in length. In embodiments, the double-stranded region is 17 nucleobase pairs in length. In embodiments, the double-stranded region is 18 nucleobase pairs in length. In embodiments, the double-stranded region is 19 nucleobase pairs in length. In embodiments, the double-stranded region is 20 nucleobase pairs in length. In embodiments, the double-stranded region is 21 nucleobase pairs in length. In embodiments, the double-stranded region is 22 nucleobase pairs in length. In embodiments, the double-stranded region is 23 nucleobase pairs in length. In embodiments, the double-stranded region is 24 nucleobase pairs in length. In embodiments, the double-stranded region is 25 nucleobase pairs in length. In embodiments, the nucleotide sequence of a sense strand has no more than one mismatch to the nucleotide sequence of an antisense strand of a double-stranded nucleic acid. In embodiments, the nucleotide sequence of a sense strand has no mismatches to the nucleotide sequence of an antisense strand of a double-stranded nucleic acid. Single-stranded nucleotide overhangs and nucleotide linkers are not considered for the purposes of determining the number of mismatches within the double-stranded region of a double-stranded nucleic acid provided herein. For example, a double-stranded nucleic acid comprising an antisense strand that is 23 nucleotides in length, and a sense strand that is 21 nucleotides in length have no mismatches over the double-stranded region, provided the nucleotide sequence of the sense strand is fully complementary over its length the nucleotide sequence of the antisense strand. Alternatively, a double-stranded nucleic acid comprising a sense strand that is 20 nucleotides in length, an antisense strand that is 22 nucleotides in length, and a nucleotide linker that is eight nucleotides in length, may have no mismatches over the double-stranded region provided the nucleotide sequence of the sense strand is fully complementary over its length to the nucleotide sequence of the antisense strand. In embodiments, a double-stranded nucleic acid comprises an antisense strand of 19 nucleotides in length and a sense strand of 19 nucleotides in length. In embodiments, the antisense strand is 22 nucleotides in length and the sense strand is 20 nucleotides in length. In embodiments, the antisense strand is 23 nucleotides in length and the sense strand is 21 nucleotides in length. In embodiments, the antisense strand is 23 nucleotides in length including two deoxythymidines at the 3’ terminus, and the sense strand is 21 nucleotides in length including two deoxythymidines at the 3’ terminus. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 16 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 17 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 18 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 19 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 20 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 21 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 23 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 24 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to 25 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 95% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand comprises at least 15 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75. In embodiments, the nucleotide sequence of antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20, or 21 nucleotides of a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75. In embodiments, the nucleotide sequence of antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75. In embodiments, the nucleotide sequence of the antisense strand comprises at least 15 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 213, 215, 217, 224, 241, 226, 228, and 230. In embodiments, the nucleotide sequence of antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20, or 21 nucleotides of a nucleotide sequence selected from SEQ ID NO: 213, 215, 217, 224, 241, 226, 228, and 230. In embodiments, the nucleotide sequence of antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 213, 215, 217, 224, 241, 226, 228, and 230. In embodiments, the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75. In embodiments, the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75, and wherein the nucleotide sequence of the antisense strand is 100% complementary to 23 contiguous nucleotides of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the sense strand comprises 19 contiguous of a nucleotide sequence selected from SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74. In embodiments, the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74. In embodiments, the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74. In embodiments, the sense strand is 21 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1. In embodiments, the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236. In embodiments, the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236, and wherein the nucleotide sequence of the antisense strand is 100% complementary to 23 contiguous nucleotides of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the sense strand comprises 19 contiguous of a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236. In embodiments, the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236. In embodiments, the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236. In embodiments, the sense strand is 21 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 16 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 17 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 18 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 19 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 20 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 21 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 23 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 24 nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to 25 contiguous nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 95% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand comprises at least 15 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 93, 95, and 97. In embodiments, nucleotide sequence of antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20, or 21 nucleotides of a nucleotide sequence selected from SEQ ID NO: 93, 95, and 97. In embodiments, the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 93, 95, and 97. In embodiments, the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 93, 95, and 97. In embodiments, the antisense strand is 23 nucleotides in length and comprises a nucleotide sequence identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96, and wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1. In embodiments, the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96. In embodiments, the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96. In embodiments, the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96. In embodiments, the sense strand is 21 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 16 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 17 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 18 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 19 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 20 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 21 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 23 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 24 nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to 25 contiguous nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 95% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand comprises at least 15 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109. In embodiments, nucleotide sequence of antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20, or 21 nucleotides of a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109. In embodiments, the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109. In embodiments, the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109. In embodiments, the antisense strand is 23 nucleotides in length and comprises a nucleotide sequence identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109, and wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1. In embodiments, the nucleotide sequence of the sense strand comprises 19 contiguous of a nucleotide sequence selected from SEQ ID NO: 8, 10, 2, 4, 104, 106, and 108. In embodiments, the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 8, 10, 2, 4, 104, 106, and 108. In embodiments, the sense strand is 19 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 8, 10, 2, 4, 104, 106, and 108. In embodiments, the sense strand is 21 nucleotides in length and comprises a nucleotide sequence comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 8, 10, 2, 4, 104, 106, and 108, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the sense strand comprises 19 contiguous of a nucleotide sequence selected from SEQ ID NO: 268 and 269. In embodiments, the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 268 and 269. In embodiments, the sense strand is 19 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 268 and 269. In embodiments, the sense strand is 21 nucleotides in length and comprises a nucleotide sequence comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 268 and 269, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1.In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 16 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 17 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 18 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 19 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 20 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 21 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 23 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 24 nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to 25 contiguous nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 95% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand comprises at least 15 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119. In embodiments, nucleotide sequence of antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20, or 21 nucleotides of a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119. In embodiments, the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119. In embodiments, the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119. In embodiments, the antisense strand is 23 nucleotides in length and comprises a nucleotide sequence identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119, wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1. In embodiments, the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 114, 116, and 118. In embodiments, the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 114, 116, and 118. In embodiments, the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 114, 116, and 118. In embodiments, the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 114, 116, and 118, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1.In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 16 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 17 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 18 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 19 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 20 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 21 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 23 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 24 nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to 25 contiguous nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 95% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand comprises at least 15 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133. In embodiments, nucleotide sequence of antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20, or 21 nucleotides of the antisense strand of a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133. In embodiments, the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133. In embodiments, the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133. In embodiments, the antisense strand is 23 nucleotides in length and comprises a nucleotide sequence identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133, and wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1. In embodiments, the nucleotide sequence of the sense strand comprises 19 linked nucleotides of a nucleotide sequence selected from SEQ ID NO: 128, 130, and 132. In embodiments, the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 128, 130, and 132. In embodiments, the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 128, 130, and 132. In embodiments, the sense strand is 21 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 128, 130, and 132, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the sense strand comprises 19 linked nucleotides of the nucleotide sequence of SEQ ID NO: 237. In embodiments, the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to the nucleotide sequence of SEQ ID NO: 237. In embodiments, the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of the nucleotide sequence of SEQ ID NO: 237. In embodiments, the sense strand is 21 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of the nucleotide sequence of SEQ ID NO: 237, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1.In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 16 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 17 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 18 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 19 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 20 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 21 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 23 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 24 nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to 25 contiguous nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 95% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand comprises at least 15 contiguous nucleotides of nucleotides of SEQ ID NO: 141. In embodiments, the nucleotide sequence of antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20, or 21 nucleotides of SEQ ID NO: 141. In embodiments, the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence of SEQ ID NO: 141. In embodiments, the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to the nucleotide sequence of SEQ ID NO: 141. In embodiments, the antisense strand is 23 nucleotides in length and comprises a nucleotide sequence identical to nucleotides 1 to 19 of the nucleotide sequence of SEQ ID NO: 141, and wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1. In embodiments, the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 140. In embodiments, the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to the nucleotide sequence of SEQ ID NO: 140. In embodiments, the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to the nucleotide sequence of SEQ ID NO: 140. In embodiments, the sense strand is 21 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of the nucleotide sequence of SEQ ID NO: 140, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 16 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 17 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 18 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 19 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 20 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 21 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 23 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 24 nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to 25 contiguous nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 95% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to the recited region of SEQ ID NO: 1. In embodiments, the antisense strand comprises at least 15 contiguous nucleotides of the antisense strand of a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19. In embodiments, the antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20 or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19. In embodiments, the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19. In embodiments, the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to the nucleotide sequence of a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19. In embodiments, the antisense strand is 23 nucleotides in length and comprises a nucleotide sequence identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19, and wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1. In embodiments, the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 170, 172, 22, 12, 14, 16, and 18. In embodiments, the nucleotide sequence of the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical a nucleotide sequence selected from SEQ ID NO: 170, 172, 22, 12, 14, 16, and 18. In embodiments, the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID: 170, 172, 22, 12, 14, 16, and 18. In embodiments, the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID: 170, 172, 22, 12, 14, 16, and 18, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 238, 273, 270, 271, and 272. In embodiments, the nucleotide sequence of the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical a nucleotide sequence selected from SEQ ID NO: 238, 273, 270, 271, and 272. In embodiments, the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID: 238, 273, 270, 271, and 272. In embodiments, the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID: 238, 273, 270, 271, and 272, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 16 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 17 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 18 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 19 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 20 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 21 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 23 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to at least 22 contiguous nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 24 nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the antisense strand is at least 90% complementary to 25 contiguous nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is at least 95% complementary to the recited region of SEQ ID NO: 1. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to the recited region of SEQ ID NO: 1. In embodiments, the antisense strand comprises at least 15 contiguous nucleotides of the antisense strand of a nucleotide sequence selected from SEQ ID NO: 193 and 195. In embodiments, the antisense strand comprises at least 16, at least 17, at least 18, at least 19, at least 20 or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 193 and 195. In embodiments, the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 193 and 195. In embodiments, the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 193 and 195. In embodiments, the antisense strand is 23 nucleotides in length and comprises a nucleotide sequence identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 193 and 195, and wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1. In embodiments, the nucleotide sequence of the sense strand comprises 19 contiguous of a nucleotide sequence selected from SEQ ID NO: 193 and 195. In embodiments, the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 192 and 194. In embodiments, the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from from SEQ ID NO: 192 and 194. In embodiments, the sense strand is 21 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 192 and 194, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide region of SEQ ID NO: 1. In embodiments of compound comprising double-stranded nucleic acid where the antisense strand and sense strand are separate strands that are not covalently linked, the terminal nucleotides may form a nucleobase pair, in which case the end of the double-stranded nucleic acid is a blunt end. Alternatively, one or more unpaired nucleotides of an antisense strand and/or sense strand may extend beyond the terminus of the complementary strand, resulting in a nucleotide overhang of one or more terminal single-stranded nucleotides. In embodiments, at least one of the 5’ and 3’ terminus of a double-stranded nucleic acid is a blunt end. In embodiments, both the 5’ terminus and 3’ terminus of the double-stranded nucleic acid are blunt ends. In embodiments, at least one end of the double-stranded nucleic acid comprises a nucleotide overhang. In embodiments, each end of the double-stranded nucleic acid comprises a nucleotide overhang. In embodiments, one end of the double-stranded nucleic acid is a blunt end and the other end of the double-stranded nucleic acid comprises a nucleotide overhang. In embodiments, the antisense strand comprises a nucleotide overhang at its 3’ terminus. In embodiments, the sense strand comprises a nucleotide overhang at its 3’ terminus. In embodiments, each of the antisense strand and sense strand comprises a nucleotide overhang at its 3’ terminus. In embodiments, at least one of the antisense strand and sense strand comprises a nucleotide overhang at its 5’ terminus. In embodiments, each of the antisense strand and sense strand comprises a nucleotide overhang at each 5’ terminus. In embodiments, a nucleotide overhang is from one to five single-stranded nucleotides. In embodiments, a nucleotide overhang is one single-stranded nucleotide. In embodiments, a nucleotide overhang is two single-stranded nucleotides. In embodiments, a nucleotide overhang is three single-stranded nucleotides. In embodiments, a nucleotide overhang is three single-stranded nucleotides. In embodiments, a nucleotide overhang is four single-stranded nucleotides. In embodiments, a nucleotide overhang is five single-stranded nucleotides. In embodiments, at least one of the single-stranded nucleotides of a nucleotide overhang is a modified nucleotide. In embodiments, each of the single-stranded nucleotides of a nucleotide overhang is a modified nucleotide. In embodiments, the modified nucleotide is a 2’-O-methyl nucleotide. In embodiments, the nucleotide overhang is two single-stranded nucleotides, and each nucleotide is a 2’-O-methoxyethyl nucleotide. In embodiments, at least one nucleotide of the nucleotide overhang at the 3’ terminus of an antisense strand is complementary to a corresponding nucleotide of SEQ ID NO: 1. In embodiments, each nucleotide of the nucleotide overhang at the 3’ terminus of an antisense strand is complementary to a corresponding nucleotide of SEQ ID NO: 1. In some embodiment, at least one nucleotide of the nucleotide overhang at the 3’ terminus of an antisense strand is not complementary to a corresponding nucleotide of SEQ ID NO: 1. In embodiments, each nucleotide of the nucleotide overhang at the 3’ terminus of an antisense strand is not complementary to a corresponding nucleotide of SEQ ID NO: 1. In embodiments, at least one single-stranded nucleotide of a nucleotide overhang is a deoxythymidine nucleotide. In embodiments, a nucleotide overhang is two single-stranded nucleotides, and each nucleotide is a deoxythymidine nucleotide. In embodiments, the nucleotide sequence of the antisense strand comprises a nucleotide overhang of two deoxythymidine nucleotides. In embodiments, the sense strand comprises a nucleotide overhang of two deoxythymidine nucleotides. In embodiments, the antisense strand and the sense strand comprise a nucleotide overhang of two deoxythymidine nucleotides. Non-limiting examples of double-stranded nucleic acids comprising blunt ends or nucleotide overhangs are provided in Table 2 below. In the first example, where the antisense strand is 21 nucleotides in length and the sense strand is 21 nucleotides in length, and the nucleotide sequence of the antisense strand is fully complementary to the nucleotide sequence of the sense strand over the double-stranded region, the length of the double-stranded region is 19 nucleobase pairs and each terminus of the double-stranded nucleic acid has a dTdT overhang. In the second example, where the antisense strand is 21 nucleotides in length and the sense strand is 19 nucleotides in length, and the nucleotide sequence of the antisense strand is fully complementary to the nucleotide sequence of the sense strand over the double-stranded region, the length of the double-stranded region is 19 nucleobase pairs and the 3’ terminus of the antisense strand comprises a dTdT overhang. In the third example, where the antisense strand is 19 nucleotides in length and the sense strand is 19 nucleotides in length, and the nucleotide sequence of the antisense strand is fully complementary to the nucleotide sequence of the sense strand over the double-stranded region, the length of the double-stranded region is 19 nucleobase pairs, and each terminus is a blunt end. In the fourth example, where the antisense strand is 23 nucleotides in length and the sense strand is 21 nucleotides in length, the length of the double-stranded region is 21 nucleobase pairs and 3’ terminus of the antisense strand comprises a two-nucleotide overhang. Table 2: Examples of double-stranded nucleic acids In embodiments of a double-stranded nucleic acid comprising a nucleotide linker, the termini that are not connected by the nucleotide linker may form a blunt end or may form a nucleotide overhang of one or more single-stranded nucleotides. In embodiments, the non-linked end of the double-stranded nucleic acid is a blunt end. In embodiments, the non-linked end comprises a nucleotide overhang of one or more single-stranded nucleotides. In embodiments, the non-linked end of the guide strand comprises a nucleotide overhang. In embodiments, the non-linked end of the sense strand comprises a nucleotide overhang. In embodiments, the 3’ terminus of the guide strand comprises a nucleotide overhang. In embodiments, the 3’ terminus of the sense strand comprises a nucleotide overhang. In embodiments, the 5’ terminus of the sense strand comprises a nucleotide overhang. In embodiments, the 5’ terminus of the sense strand comprises a nucleotide overhang. In embodiments of a double-stranded nucleic acid where the antisense and sense strand are covalently linked by a nucleotide linker, the nucleotide linker is four to 16 nucleotides in length. In embodiments, the nucleotide linker is four nucleotides in length. In embodiments, the nucleotide linker is four nucleotides in length. In embodiments, the nucleotide linker is five nucleotides in length. In embodiments, the nucleotide linker is six nucleotides in length. In embodiments, the nucleotide linker is seven nucleotides in length. In embodiments, the nucleotide linker is eight nucleotides in length. In embodiments, the nucleotide linker is nine nucleotides in length. In embodiments, the nucleotide linker is 10 nucleotides in length. In embodiments, the nucleotide linker is 11 nucleotides in length. In embodiments, the nucleotide linker is 12 nucleotides in length. In embodiments, the nucleotide linker is 13 nucleotides in length. In embodiments, the nucleotide linker is 14 nucleotides in length. In embodiments, the nucleotide linker is 15 nucleotides in length. In embodiments, the nucleotide linker is 16 nucleotides in length. Although the sequence listing accompanying this filing identifies each nucleotide sequence as either "RNA" or "DNA" as required, in practice, those sequences may be modified with a combination of chemical modifications specified herein. One of skill in the art will readily appreciate that in the sequence listing, such designation as "RNA" or "DNA" to describe modified nucleotides is somewhat arbitrary. For example, a nucleic acid provided herein comprising a nucleotide comprising a 2'-O-methyl sugar moiety and a thymine base may described as a DNA residue in the sequence listing, even though the nucleotide is modified and is not a naturally-occurring DNA nucleotide. Accordingly, nucleic acid sequences provided in the sequence listing are intended to encompass nucleic acids containing any combination of natural or modified RNA and/or DNA, including, but not limited to such nucleic acids having modified nucleobases. By way of further example and without limitation, a nucleic acid having the nucleotide sequence "ATCGATCG" in the sequence listing encompasses any nucleic acid having such nucleotide sequence, whether modified or unmodified, including, but not limited to, such nucleic acids comprising RNA bases, such as those having sequence "AUCGAUCG" and those having some DNA bases and some RNA bases such as "AUCGATCG" and oligonucleotides having other modified bases, such as "ATmeCGAUCG," wherein meC indicates a 5-methylcytosine. Modified Nucleotides Double-stranded and single-stranded nucleic acids provided herein may comprise one or more modified nucleotides. A modified nucleotide may be selected over an unmodified form because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for other oligonucleotides or nucleic acid targets, increased stability in the presence of nucleases, and/or reduced immune stimulation. In embodiments, at least one nucleotide of the antisense strand is a modified nucleotide. In embodiments, at least one nucleotide of the sense strand is a modified nucleotide. In embodiments, each nucleotide of the antisense strand forming the double-stranded region is a modified nucleotide. In embodiments, each nucleotide of the sense strand forming the double-stranded region comprises is a modified nucleotide. In embodiments, a modified nucleotide comprises one or more of a modified sugar moiety, a modified internucleotide linkage, and a 5’-terminal modified phosphate group. In embodiments, a modified nucleotide comprises a modified sugar moiety. In embodiments, a modified nucleotide comprises a modified internucleotide linkage. In embodiments, a modified nucleotide comprises a modified nucleobase. In embodiments, a modified nucleotide comprises a modified 5’-terminal phosphate group. In embodiments, a modified nucleotide comprises a modification at the 5’ carbon of the pentafuranosyl sugar. In embodiments, a modified nucleotide comprises a modification at the 3’ carbon of the pentafuranosyl sugar. In embodiments, a modified nucleotide comprises a modification at the 2’ carbon of the pentafuranosyl sugar. In embodiments, a modified nucleotide is at the 5’ terminus of an antisense strand or sense strand. In embodiments, a modified nucleotide is at the 3’ terminus of an antisense strand or sense strand. In embodiments, a modified nucleotide is at an internal nucleotide of an antisense strand or sense strand. In embodiments, a modified nucleotide comprises a ligand attached to the 2’, 3, or 5’ carbon of the pentafuranosyl sugar. In embodiments, a nucleotide comprises a ligand attached to a nucleobase. A modified nucleotide may comprise a modified sugar moiety, a naturally occurring nucleobase, and a naturally occurring internucleotide linkage. A modified nucleotide may comprise a modified sugar moiety, a naturally occurring nucleobase, and a modified internucleotide linkage. In embodiments, a modified sugar moiety is modified at the 2’ carbon of the pentafuranosyl sugar, relative to the naturally occurring 2’-OH of RNA or the 2’-H of DNA. In embodiments, a modification at the 2’ carbon of the pentafuranosyl sugar is selected from F, OCF3, OCH3 (also referred to as "2 '-OMe" or “2’-O-methyl), OCH2CH2OCH3 (also referred to as "2'-O-methoxyethyl" or "2'-MOE"), 2'-O(CH2)2SCH3, O-(CH2)2-O-N(CH3)2, -O(CH2)2O(CH2)2N(CH3)2, and O-CH2-C(=O)-N(H)CH3. In embodiments, a modified sugar moiety is a 2’-fluoro sugar (also referred to as a 2’-F sugar). In embodiments, a modified sugar moiety is a 2’-O-methyl sugar (also referred to as a "2 '-OMe sugar" or a “2’-OCH3” sugar). In embodiments, a modified sugar moiety is a 2’-O-methoxyethyl sugar (also referred to as a 2’-OCH2CH2OCH3 or a 2’-MOE sugar). In embodiments, the modified nucleotide comprising a modified sugar moiety is selected from a 2’-fluoro nucleotide, a 2’-O-methyl nucleotide, a 2’-O-methoxyethyl nucleotide, and a bicyclic sugar nucleotide. In embodiments, a modified nucleotide is a 2’-fluoro nucleotide, where the 2’ carbon of the pentafuranosyl sugar has a fluoro substitution. In embodiments, a modified nucleotide is a 2’-O-methyl nucleotide, where the 2’ carbon of the pentafuranosyl sugar has a 2’-O methyl substitution. In embodiments, a modified nucleotide is a 2’-O-methoxyethyl nucleotide, where the 2’ carbon of the pentafuranosyl sugar has a 2’-O-methoxyethyl substitution. Other modified nucleotides may be similarly named. In embodiments, a modified nucleotide comprises a modified sugar moiety, where the ribose has a covalent linkage between the 2’ and 4’ carbons. Such a modified sugar moiety may be referred to as a “bicyclic sugar,” and nucleotides comprising such sugar moieties may be referred to as “bicyclic nucleic acids.” In embodiments, the covalent linkage of a bicyclic sugar is a methyleneoxy linkage (4'-CH2-O-2'), also known as “LNA.” In embodiments, the covalent linkage of a bicyclic sugar is an ethyleneoxy linkage (4'-(CH2)2-O-2'), also known as “ENA.” In embodiments, the covalent linkage of a bicyclic moiety is a methyl(methyleneoxy) linkage (4'-CH(CH3)-O-2'), also known as “constrained ethyl” or “cEt.” In certain embodiments, the -CH(CH3)- bridge is constrained in the S orientation (“S-cEt”). In certain embodiments, the -CH(CH3)- bridge is constrained in the R orientation (“R-cEt”). In embodiments, the covalent linkage of a bicyclic sugar is a (4'-CH(CH2-OMe)-O-2' linkage, also known as “c-MOE.” In embodiments, the bicyclic sugar is a D sugar in the alpha configuration. In certain such embodiments, the bicyclic sugar is a D sugar in the beta configuration. In certain such embodiments, the bicyclic sugar is an L sugar in the alpha configuration. In certain such embodiments, the bicyclic sugar is an L sugar in the beta configuration. In embodiments, a modified sugar moiety is a 1,5-anhydrohexitol nucleic acid, also known as a “hexitol nucleic acid” or “HNA.” In embodiments, the oxygen of the pentafuranosyl sugar is replace with a sulfur, to form a thio-sugar. In embodiments, a thio-sugar is modified at the 2’ carbon. In embodiments, a modified internucleotide linkage is a phosphorothioate internucleotide linkage. In embodiments, a modified internucleotide linkage is a methylphosphonate internucleotide linkage. In embodiments, the first two internucleotide linkages at the 5’ terminus of the sense strand and the last two internucleotide linkages at the 3’ terminus of the sense strand are phosphorothioate internucleotide linkages. In embodiments, the first two internucleotide linkages at the 5’ terminus of the antisense strand and the last two internucleotide linkages at the 3’ terminus of the antisense strand are phosphorothioate internucleotide linkages. In embodiments, the first two internucleotide linkages at the 5’ terminus of the sense strand and the last two internucleotide linkages at the 3’ terminus of the sense strand are phosphorothioate internucleotide linkages, and the first two internucleotide linkages at the 5’ terminus of the antisense strand and the last two internucleotide linkages at the 3’ terminus of the antisense strand are phosphorothioate internucleotide linkages. In embodiments, a modified nucleobase is selected from 5-hydroxymethyl cytosine, 7-deazaguanine and 7-deazaadenine. In embodiments, a modified nucleobase is selected from 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. In embodiments, a modified nucleobase is selected from 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2 aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. In embodiments, a modified nucleotide comprises a modification of the phosphate group at the 4’-carbon of the pentafuranosyl sugar. In embodiments, the modified phosphate group is 5’-(E)-vinylphosphonate. In embodiments, a modified nucleotide is a phosphorodiamidite-linked morpholino nucleotide. In embodiments, a modified nucleotide comprises an acyclic nucleoside derivative lacking the bond between the 2’ carbon and 3’ carbon of the sugar ring, also known as an “unlocked nucleic acid” or “UNA.” In embodiments, the antisense strand is 21 nucleotides in length and the nucleotides of the antisense strand are modified such that, counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides, and nucleotides 20 and 21 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by the following Formula I: 5’-NMSNFSNMNFNMNFNMNFNMNFNMNFNMNFNMNFNMNFNMSNSN-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, “N” is a beta-D-deoxynucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In embodiments, the sense strand is 21 nucleotides in length and the nucleotides of the sense strand are modified such that, counting from the from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides, and nucleotides 20 and 21 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by the following Formula II: 5’-NFSNMSNFNMNFNMNFNMNFNMNFNMNFNMNFNMNFNMNFSNSN-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, “N” is a beta-D-deoxynucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In embodiments, the antisense strand is 19 nucleotides in length and the nucleotides of the antisense strand are modified such that, counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by the following Formula III: 5’-NM SNF SNMNFNMNFNMNFNMNFNMNFNMNFNMNFNM SNF SNM-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, “N” is a beta-D-deoxynucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkages is a phosphodiester internucleotide linkage. In embodiments, the sense strand is 19 nucleotides in length and the nucleotides of the sense strand are modified such that, counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoro nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by the following Formula IV: 5’-NFSNMSNFNMNFNMNFNMNFNMNFNMNFNMNFNMNFSNMSNF-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, “N” is a beta-D-deoxynucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphorodiester internucleotide linkage. In embodiments, the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-fluoro nucleotides the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by the following Formula V: 5’-NM SNF SNMNFNMNFNMNFNMNFNMNFNMNFNMNFNMNFNMNFNM SNM SNM-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In embodiments, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by the Formula VI: 5’-NF SNM SNFNMNFNMNFNMNFNMNFNMNFNMNFNMNFNMNF SNM SNF-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In embodiments, the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by the Formula VII: 5’-NMSNFSNMNFNMNFNMNFNMNFNMNMNMNFNMNFNMNFNMNFNMSNMSNM-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In embodiments, the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by the Formula VIII: 5’-NFSNMSNFNMNFNMNFNMNFNFNFNMNFNMNFNMNFNMNFSNMSNF-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In embodiments, the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by the Formula IX: 5’-NM SNF SNMNFNMNFNMNFNMNMNMNFNMNFNMNFNMNFNMNFNM SNM SNM-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In embodiments, the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by the Formula X: 5’-NFSNMSNFNMNFNMNFNMNFNMNFNFNFNMNFNMNFNMNFSNMSNF-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In embodiments, wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by the Formula XI: 5’-NF SNM SNFNMNFNMNFNMNFNMNFNMNFNMNFNMNFNMNFNMNF SNSN-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, “N” is a beta-D-deoxynucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In embodiments, the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by the Formula XII: 5’-NFSNMSNFNMNFNMNFNMNFNFNFNMNFNMNFNMNFNMNFNMNFSNSN-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, “N” is a beta-D-deoxynucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In embodiments, the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by the Formula XIII: 5’-NF SNM SNFNMNFNMNFNMNFNMNFNFNFNMNFNMNFNMNFNMNF SNSN-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, “N” is a beta-D-deoxynucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In embodiments, the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by the Formula XIV: 5’-NM SNM SNFNMNFNMNFNMNFNMNFNMNFNMNFNMNFNMNF SNM SNF-3', wherein “NM” is a 2’-O-methyl nucleotide, “NF” is a 2’-fluoro nucleotide, a superscript “S” is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In embodiments, a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded region, wherein the antisense strand and sense strand are not covalently linked (i.e. the antisense strand and sense strand form an siRNA), wherein the antisense strand is 21 nucleotides in length and the nucleotides of the antisense strand are modified such that, counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides, and nucleotides 20 and 21 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 21 nucleotide in length and the nucleotides of the sense strand are modified such that, counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides, and nucleotides 20 and 21 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In such embodiments, the antisense strand has the modification pattern represented by Formula I and the sense strand has the modification pattern represented by Formula II. In embodiments, a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e. the antisense strand and sense strand form an siRNA), wherein the antisense strand is 19 nucleotides in length and the nucleotides of the antisense strand are modified such that, counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 21 nucleotide in length and the nucleotides of the sense strand are modified such that, counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides, and nucleotides 20 and 21 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In such embodiments, the antisense strand has the modification pattern represented by Formula III and the sense strand has the modification pattern represented by Formula II. In embodiments, a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e. the antisense strand and sense strand form an siRNA), wherein the antisense strand is 21 nucleotides in length and the nucleotides of the antisense strand are modified such that, counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides, and nucleotides 20 and 21 are beta-D-deoxy nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 19 nucleotide in length and the nucleotides of the sense strand are modified such that, counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoro nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In such embodiments, the antisense strand has the modification pattern represented by Formula I and the sense strand has the modification pattern represented by Formula IV. In embodiments, a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e. the antisense strand and sense strand form an siRNA), wherein the antisense strand is 19 nucleotides in length and the nucleotides of the antisense strand are modified such that, counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide is a phosphodiester internucleotide linkage; and wherein the sense strand is 19 nucleotides in length and the nucleotides of the sense strand are modified such that, counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoro nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In such embodiments, the antisense strand has the modification pattern represented by Formula III and the sense strand has the modification pattern represented by Formula IV. In embodiments, a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e. the antisense strand and sense strand form an siRNA), wherein the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-fluoro nucleotides the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 21 nucleotides in length and the nucleotides of the sense strand are modified such that, counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In such embodiments, the antisense strand has the modification pattern represented by Formula V and the sense strand has the modification represented by Formula VI. In embodiments, a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e. the antisense strand and sense strand form an siRNA), wherein the antisense strand is 23 nucleotides in length and wherein the nucleotides of the antisense strand are modified such that counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 21 nucleotides in length and the nucleotides of the sense strand are modified such that counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In such embodiments, the antisense strand has the modification pattern represented by Formula VII and the sense strand has the modification pattern represented by Formula VIII. In embodiments, a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e. the antisense strand and sense strand form an siRNA), wherein the antisense strand is 23 nucleotides in length and wherein the nucleotides of the antisense strand are modified such that counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages ,and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 21 nucleotides in length and nucleotides of the sense strand are modified such that counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2’-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In such embodiments, the antisense strand has the modification pattern of Formula IX and the sense strand has the modification pattern of Formula X. In embodiments, a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e. the antisense strand and sense strand form an siRNA), wherein the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-fluoro nucleotides the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In such embodiments, the antisense strand has the modification pattern represented by Formula V and the sense strand has the modification represented by Formula XI. In embodiments, a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e. the antisense strand and sense strand form an siRNA), wherein the antisense strand is 23 nucleotides in length and wherein the nucleotides of the antisense strand are modified such that counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2’-fluoro nucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In such embodiments, the antisense strand has the modification pattern represented by Formula VII and the sense strand has the modification pattern represented by Formula XII. In embodiments, a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e. the antisense strand and sense strand form an siRNA), wherein the antisense strand is 23 nucleotides in length and wherein the nucleotides of the antisense strand are modified such that counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-fluoro nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages ,and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2’-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In such embodiments, the antisense strand has the modification pattern of Formula IX and the sense strand has the modification pattern of Formula XIII. In embodiments, a compound comprises an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein the antisense strand and sense strand are not covalently linked (i.e. the antisense strand and sense strand form an siRNA), wherein the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methyl nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-fluoro nucleotides the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and wherein the sense strand is 21 nucleotides in length and the nucleotides of the sense strand are modified such that, counting from the 5’ terminus of the sense strand, nucleotides 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoro nucleotides, nucleotides 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In such embodiments, the antisense strand has the modification pattern represented by Formula V and the sense strand has the modification represented by Formula XIV. In embodiments, a compound comprises an siRNA described herein. In embodiments, a compound is selected from DT-000469, DT-000470, DT-000118, DT-000362, DT-000363, DT-000364, DT-000365, DT-000120, DT-000366, DT-000367, DT-000368, DT-000369, DT-000370, DT-000371, DT-000372, DT-000373, DT-000119, DT-000374, DT-000375, DT-000376, DT-000471, DT-000472, DT-000473, DT-000474, DT-000475, DT-000484, DT-000485, DT-000486, DT-000110, DT-000111, DT-000107, DT-000108, DT-000490, DT-000491, DT-000492, DT-000502, DT-000503, DT-000504, DT-000505, DT-000506, DT-000507, DT-000508, DT-000495, DT-000496, DT-000497, DT-000502, DT-000503, DT-000504, DT-000508, DT-000523, DT-000524, DT-000117, DT-000112, DT-000113, DT-000114, DT-000115, DT-000534, DT-000535, DT-000726, DT-000727, DT-000734, DT-000782, DT-000783, and DT-000784. In embodiments, a compound is selected from DT- 001373, DT-001374, DT-001375, and DT-001386. In embodiments, the compound is DT-000469. In embodiments, the compound is DT-000470. In embodiments, the compound is DT-000118. In embodiments, the compound is DT-000362. In embodiments, the compound is DT-000363. In embodiments, the compound is DT-000364. In embodiments, the compound is DT-000365. In embodiments, the compound is selected DT-000120. In embodiments, the compound is DT-000366. In embodiments, the compound is DT-000367. In embodiments, the compound is DT-000368. In embodiments, the compound is DT-000369. In embodiments, the compound is DT-000369. In embodiments, the compound is DT-000370. In embodiments, the compound is DT-000371. In embodiments, the compound is DT-000372. In embodiments, the compound is DT-000373. In embodiments, the compound is DT-000119. In embodiments, the compound is DT-000374. In embodiments, the compound is DT-000375. In embodiments, the compound is DT-000376. In embodiments, the compound is DT-000471. In embodiments, the compound is DT-000472. In embodiments, the compound is DT-000473. In embodiments, the compound is DT-000474. In embodiments, the compound is DT-000475. In embodiments, the compound is DT-000484. In embodiments, the compound is DT-000485. In embodiments, the compound is DT-000486. In embodiments, the compound is DT-000110. In embodiments, the compound is DT-000111. In embodiments, the compound is DT-000107. In embodiments, the compound is DT-000108. In embodiments, the compound is DT-000490. In embodiments, the compound is DT-000491. In embodiments, the compound is DT-000492. In embodiments, the compound is DT-000495. In embodiments, the compound is DT-000496. In embodiments, the compound is DT-000497. In embodiments, the compound is DT-000502. In embodiments, the compound is DT-000503. In embodiments, the compound is DT-000504. In embodiments, the compound is DT-000508. In embodiments, the compound is DT-000523. In embodiments, the compound is DT-000524. In embodiments, the compound is DT-000117. In embodiments, the compound is DT-000112. In embodiments, the compound is DT-000113. In embodiments, the compound is DT-000114. In embodiments, the compound is DT-000115. In embodiments, the compound is DT-000534. In embodiments, the compound is DT-000535. In embodiments, the compound is DT-000726. In embodiments, the compound is DT-000727. In embodiments, the compound is DT-000734. In embodiments, the compound is DT-000782. In embodiments, the compound is DT-000783. In embodiments, the compound is DT-000784. In embodiments, the compound is DT-001373. In embodiments, the compound is DT-001374. In embodiments, the compound is DT-001375. In embodiments, the compound is DT-001386. In embodiments, a compound comprises an siRNA described herein, wherein each antisense strand has the modification pattern of Formula I, and each sense strand of has the modification pattern of Formula IV. In embodiments, a compound comprises an siRNA described herein, wherein each antisense strand has the modification pattern of Formula V and each sense strand has the modification pattern of Formula VI. In embodiments, a compound comprises an siRNA described herein, wherein each antisense strand has the modification pattern of Formula VII and each sense strand has the modification pattern of Formula VIII. In embodiments, a compound comprises an siRNA described herein, wherein each antisense strand has the modification pattern of Formula IX and each sense strand has the modification pattern of Formula X. In embodiments, a compound comprises an siRNA described herein, wherein each antisense strand has the modification pattern of Formula a compound comprises an siRNA described herein, wherein each antisense strand has the modification pattern of Formula IX and each sense strand has the modification pattern of Formula X and each sense strand has the modification pattern of Formula XIV. In embodiments, a compound provided herein comprises a covalently linked ligand. In embodiments, a compound provided herein comprises a ligand covalently linked to the antisense strand. In embodiments, a compound provided herein comprises a ligand covalently linked to the sense strand. In embodiments, the ligand comprises an uptake motif with one or more long chain fatty acids (LFCA). In embodiments, a compound comprising an uptake motif has the structure (I) wherein A is a double-stranded nucleic acid and t is an integer from 1 to 5. In embodiments, A is the sense strand. In embodiments, A is the antisense strand. L3 and L4 are independently a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, -C(O)N(R24)-, -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O-P(S)(NR23R24)-N-, -O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-, -S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene. Each R23, R24 and R25 is independently hydrogen or unsubstituted C1-C10 alkyl. L5 is -L5A-L5B-L5C-L5D-L5E- and L6 is -L6A-L6B-L6C-L6D-L6E-. L5A, L5B, L5C, L5D, L5E, L6A, L6B, L6C, L6D, and L6E are independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, –C(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene. R1 and R2 are independently unsubstituted C1-C25 alkyl, wherein at least one of R1 and R2 is unsubstituted C9-C19 alkyl. In embodiments, R1 and R2 are independently unsubstituted C1-C20 alkyl, wherein at least one of R1 and R2 is unsubstituted C9-C19 alkyl. R3 is hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, t is 1. In embodiments, t is 2. In embodiments, t is 3. In embodiments, t is 4. In embodiments, t is 5. In embodiments, one L3 is attached to a 3’ carbon of a nucleotide. In embodiments, one L3 is attached to the 3’ carbon the 3’ terminal nucleotide of the sense strand. In embodiments, one L3 is attached to the 3’ carbon of the 3’ terminal nucleotide of the antisense strand. In embodiments, one L3 is attached to a 5’ carbon of a nucleotide. In embodiments, one L3 is attached to the 5’ carbon of the 5’ terminal nucleotide of the sense strand. In embodiments, one L3 is attached to the 5’ carbon of the 5’ terminal nucleotide of the antisense strand. In embodiments, one L3 is attached to a 2’ carbon of a nucleotide. In embodiments, one L3 is attached to a 2’ carbon of a nucleotide of the sense strand. In embodiments, one L3 is attached to a 2’ carbon of a nucleotide of the antisense strand. In embodiments, one L3 is attached to a nucleobase. In embodiments, one L3 is attached to a nucleobase of the sense strand. In embodiments, one L3 is attached to a nucleobase of the antisense strand. In embodiments, one L3 is attached to a phosphate group at a 3’ carbon of a nucleotide. In embodiments, one L3 is attached to a phosphate group at the 3’ carbon the 3’ terminal nucleotide of the sense strand. In embodiments, one L3 is attached to a phosphate group at the 3’ carbon of the 3’ terminal nucleotide of the antisense strand. In embodiments, one L3 is attached to a phosphate group at a 5’ carbon of a nucleotide. In embodiments, one L3 is attached to a phosphate group at the 5’ carbon of the 5’ terminal nucleotide of the sense strand. In embodiments, one L3 is attached to a phosphate group at the 5’ carbon of the 5’ terminal nucleotide of the antisense strand. In embodiments, one L3 is attached to a phosphate group at a 2’ carbon of a nucleotide. In embodiments, one L3 is attached to a phosphate group at a 2’ carbon of a nucleotide of the sense strand. In embodiments, one L3 is attached to a phosphate group a 2’ carbon of a nucleotide of the antisense strand. In embodiments, L3 is a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, -C(O)N(R24)-, -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O-P(S)(NR23R24)-N-, -O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In embodiments, L3 is a bond. In embodiments, L3 is -N(R23)-. In embodiments, L3 is -O- or -S-. In embodiments, L3 is -C(O)-. In embodiments, L3 is -N(R23)C(O)- or -C(O)N(R24)-. In embodiments, L3 is -N(R23)C(O)N(R24)-. In embodiments, L3 is -C(O)O- or -OC(O)-. In embodiments, L3 is -N(R23)C(O)O- or -OC(O)N(R24)-. In embodiments, L3 is -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(O)(NR23R24)-N-, or -O-P(O)(NR23R24)-O-. In embodiments, L3 is -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, or -P(S)(NR23R24)-O-. In embodiments, L3 is -S-S-. In embodiments, L3 is independently substituted or unsubstituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L3 is independently substituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L3 is independently unsubstituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L3 is independently substituted or unsubstituted C1-C23 alkylene. In embodiments, L3 is independently substituted C1-C23 alkylene. In embodiments, L3 is independently unsubstituted C1-C23 alkylene. In embodiments, L3 is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L3 is independently substituted C1-C12 alkylene. In embodiments, L3 is independently unsubstituted C1-C12 alkylene. In embodiments, L3 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L3 is independently substituted C1-C8 alkylene. In embodiments, L3 is independently unsubstituted C1-C8 alkylene. In embodiments, L3 is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L3 is independently substituted C1-C6 alkylene. In embodiments, L3 is independently unsubstituted C1-C6 alkylene. In embodiments, L3 is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L3 is independently substituted C1-C4 alkylene. In embodiments, L3 is independently unsubstituted C1-C4 alkylene. In embodiments, L3 is independently substituted or unsubstituted ethylene. In embodiments, L3 is independently substituted ethylene. In embodiments, L3 is independently unsubstituted ethylene. In embodiments, L3 is independently substituted or unsubstituted methylene. In embodiments, L3 is independently substituted methylene. In embodiments, L3 is independently unsubstituted methylene. In embodiments, L3 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L3 is independently substituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L3 is independently unsubstituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L3 is independently substituted or unsubstituted 2 to 23 membered heteroalkylene. In embodiments, L3 is independently substituted 2 to 23 membered heteroalkylene. In embodiments, L3 is independently unsubstituted 2 to 23 membered heteroalkylene. In embodiments, L3 is independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L3 is independently substituted 2 to 8 membered heteroalkylene. In embodiments, L3 is independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L3 is independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L3 is independently substituted 2 to 6 membered heteroalkylene. In embodiments, L3 is independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L3 is independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L3 is independently substituted 4 to 6 membered heteroalkylene. In embodiments, L3 is independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L3 is independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L3 is independently substituted 2 to 3 membered heteroalkylene. In embodiments, L3 is independently unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L3 is independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L3 is independently substituted 4 to 5 membered heteroalkylene. In embodiments, L3 is independently unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L4 is a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, -C(O)N(R24)-, -N(R23)C(O)N(R24) -, -C(O)O-, -OC(O) -, -N(R23)C(O)O-, -OC(O)N(R24)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O-P(S)(NR23R24)-N-, -O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In embodiments, L4 is a bond. In embodiments, L4 is -N(R23)-. In embodiments, L4 is -O- or -S-. In embodiments, L4 is -C(O)-. In embodiments, L4 is -N(R23)C(O)- or -C(O)N(R24)-. In embodiments, L4 is -N(R23)C(O)N(R24)-. In embodiments, L4 is -C(O)O- or -OC(O)-. In embodiments, L4 is -N(R23)C(O)O- or -OC(O)N(R24)-. In embodiments, L4 is -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(O)(NR23R24)-N-, or -O-P(O)(NR23R24)-O-. In embodiments, L4 is -P(O)(NR23R24)-N-,-P(S)(NR23R24)-N-, -P(O)(NR23R24)-O- or -P(S)(NR23R24)-O-. In embodiments, L4 is -S-S-. In embodiments, L4 is independently substituted or unsubstituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4 is independently substituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4 is independently unsubstituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4 is independently substituted or unsubstituted C1-C23 alkylene. In embodiments, L4 is independently substituted C1-C23 alkylene. In embodiments, L4 is independently unsubstituted C1-C23 alkylene. In embodiments, L4 is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L4 is independently substituted C1-C12 alkylene. In embodiments, L4 is independently unsubstituted C1-C12 alkylene. In embodiments, L4 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L4 is independently substituted C1-C8 alkylene. In embodiments, L4 is independently unsubstituted C1-C8 alkylene. In embodiments, L4 is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L4 is independently substituted C1-C6 alkylene. In embodiments, L4 is independently unsubstituted C1-C6 alkylene. In embodiments, L4 is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L4 is independently substituted C1-C4 alkylene. In embodiments, L4 is independently unsubstituted C1-C4 alkylene. In embodiments, L4 is independently substituted or unsubstituted ethylene. In embodiments, L4 is independently substituted ethylene. In embodiments, L4 is independently unsubstituted ethylene. In embodiments, L4 is independently substituted or unsubstituted methylene. In embodiments, L4 is independently substituted methylene. In embodiments, L4 is independently unsubstituted methylene. In embodiments, L4 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L4 is independently substituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L4 is independently unsubstituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L4 is independently substituted or unsubstituted 2 to 23 membered heteroalkylene. In embodiments, L4 is independently substituted 2 to 23 membered heteroalkylene. In embodiments, L4 is independently unsubstituted 2 to 23 membered heteroalkylene. In embodiments, L4 is independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L4 is independently substituted 2 to 8 membered heteroalkylene. In embodiments, L4 is independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L4 is independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L4 is independently substituted 2 to 6 membered heteroalkylene. In embodiments, L4 is independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L4 is independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L4 is independently substituted 4 to 6 membered heteroalkylene. In embodiments, L4 is independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L4 is independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L4 is independently substituted 2 to 3 membered heteroalkylene. In embodiments, L4 is independently unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L4 is independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L4 is independently substituted 4 to 5 membered heteroalkylene. In embodiments, L4 is independently unsubstituted 4 to 5 membered heteroalkylene. R23 is independently hydrogen or unsubstituted alkyl (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R23 is independently hydrogen. In embodiments, R23 is independently unsubstituted C1-C23 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C12 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C10 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C8 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C2 alkyl. R24 is independently hydrogen or unsubstituted alkyl (e.g., C1-C24, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R24 is independently hydrogen. In embodiments, R24 is independently unsubstituted C1-C24 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C12 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C10 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C8 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C2 alkyl. R25 is independently hydrogen or unsubstituted alkyl (e.g., C1-C25, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R25 is independently hydrogen. In embodiments, R25 is independently unsubstituted C1-C25 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C12 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C10 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C8 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C2 alkyl. In embodiments, L3 and L4 are independently a bond, -NH-, -O-,-C(O)-, -C(O)O-, -OC(O)-, -OPO2-O- -O-P(O)(S)-O-, -O-P(O)(CH3)-O-, -O-P(S)(CH3)-O-, -O-P(O)(N(CH3)2)-N-, -O-P(O)(N(CH3)2)-O-, -O-P(S)(N(CH3)2)-N-, -O-P(S)(N(CH3)2)-O-, -P(O)(N(CH3)2)-N-, -P(O)(N(CH3)2)-O-, -P(S)(N(CH3)2)-N-, -P(S)(N(CH3)2)-O-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In embodiments, L3 is independently a bond, -NH-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(CH3)-O-, -O-P(S)(CH3)-O-, -O-P(O)(N(CH3)2)-N-, -O-P(O)(N(CH3)2)-O-, -O-P(S)(N(CH3)2)-N-, -O-P(S)(N(CH3)2)-O-, - P(O)(N(CH3)2)-N-, -P(O)(N(CH3)2)-O-, -P(S)(N(CH3)2)-N-, -P(S)(N(CH3)2)-O-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In embodiments, L4 is independently a bond, -NH-, -O-, -C(O)-, -C(O)O-, -OC(O) -, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(CH3)-O-, -O-P(S)(CH3)-O-, -O-P(O)(N(CH3)2)-N-, -O-P(O)(N(CH3)2)-O-, -O-P(S)(N(CH3)2)-N-, -O-P(S)(N(CH3)2)-O-, -P(O)(N(CH3)2)-N-, -P(O)(N(CH3)2)-O-, -P(S)(N(CH3)2)-N-, -P(S)(N(CH3)2)-O-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In embodiments, L3 is independently . In embodiments, L3 is independently -OPO2-O-. In embodiments, L3 is independently -O-P(O)(S)-O-. In embodiments, L3 is independently -O-. In embodiments, L3 is independently -S-. In embodiments, L4 is independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-. In embodiments, L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7 is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7 is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L4 is independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L4 is independently oxo-substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L4 is independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4 is independently -L7-NH-C(O)-; and L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4 is independently -L7-C(O)-NH-; and L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7 is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7 is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7 is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L7 is independently substituted C1-C20 alkylene. In embodiments, L7 is independently hydroxy(OH)-substituted C1-C20 alkylene. In embodiments, L7 is independently hydroxymethyl-substituted C1-C20 alkylene. In embodiments, L7 is independently unsubstituted C1-C20 alkylene. In embodiments, L7 is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L7 is independently substituted C1-C12 alkylene. In embodiments, L7 is independently hydroxy(OH)-substituted C1-C12 alkylene. In embodiments, L7 is independently hydroxymethyl-substituted C1-C12 alkylene. In embodiments, L7 is independently unsubstituted C1-C12 alkylene. In embodiments, L7 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L7 is independently substituted C1-C8 alkylene. In embodiments, L7 is independently hydroxy(OH)-substituted C1-C8 alkylene. In embodiments, L7 is independently hydroxymethyl-substituted C1-C8 alkylene. In embodiments, L7 is independently unsubstituted C1-C8 alkylene. In embodiments, L7 is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L7 is independently substituted C1-C6 alkylene. In embodiments, L7 is independently hydroxy(OH)-substituted C1-C6 alkylene. In embodiments, L7 is independently hydroxymethyl-substituted C1-C6 alkylene. In embodiments, L7 is independently unsubstituted C1-C6 alkylene. In embodiments, L7 is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L7 is independently substituted C1-C4 alkylene. In embodiments, L7 is independently hydroxy(OH)-substituted C1-C4 alkylene. In embodiments, L7 is independently hydroxymethyl-substituted C1-C4 alkylene. In embodiments, L7 is independently unsubstituted C1-C4 alkylene. In embodiments, L7 is independently substituted or unsubstituted C1-C2 alkylene. In embodiments, L7 is independently substituted C1-C2 alkylene. In embodiments, L7 is independently hydroxy(OH)-substituted C1-C2 alkylene. In embodiments, L7 is independently hydroxymethyl-substituted C1-C2 alkylene. In embodiments, L7 is independently unsubstituted C1-C2 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently substituted C1-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently hydroxy(OH)-substituted C1-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently hydroxymethyl-substituted C1-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently unsubstituted C1-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently substituted or unsubstituted C3-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently substituted C3-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently hydroxy(OH)-substituted C3-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently hydroxymethyl-substituted C3-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently unsubstituted C3-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently substituted or unsubstituted C5-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently substituted C5-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently hydroxy(OH)-substituted C5-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently hydroxymethyl-substituted C5-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently unsubstituted C5-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently substituted or unsubstituted octylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently substituted octylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently hydroxy(OH)-substituted octylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently unsubstituted octylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently hydroxy(OH)-substituted octylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently hydroxymethyl-substituted octylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently unsubstituted octylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently substituted or unsubstituted heptylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently substituted heptylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently hydroxy(OH)-substituted heptylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently unsubstituted heptylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently hydroxy(OH)-substituted heptylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently hydroxymethyl-substituted heptylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently unsubstituted heptylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently substituted or unsubstituted hexylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently substituted hexylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently hydroxy(OH)-substituted hexylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently unsubstituted hexylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently hydroxy(OH)-substituted hexylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently hydroxymethyl-substituted hexylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently unsubstituted hexylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently substituted or unsubstituted pentylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently substituted pentylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently hydroxy(OH)-substituted pentylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-; and L7 is independently unsubstituted pentylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently hydroxy(OH)-substituted pentylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently hydroxymethyl-substituted pentylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently unsubstituted pentylene. In embodiments, L4 is independently . In embodiments, L4 is independently . In embodiments, L4 is independently . In embodiments, L4 is independently . In embodiments, L4 is independently . In embodiments, L4 is independently . In embodiments, L4 is independently . In embodiments, L4 is independently . In embodiments, L4 is independently . , . In embodiments, -L3-L4- is independently -L7-NH-C(O)- or -L7-C(O)-NH-. In embodiments, L7 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7 is independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7 is independently oxo-substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7 is independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7 is independently substituted or unsubstituted heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7 is independently substituted heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7 is independently oxo-substituted heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7 is independently unsubstituted heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7 is independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L7 is independently substituted 2 to 20 membered heteroalkylene. In embodiments, L7 is independently oxo-substituted 2 to 20 membered heteroalkylene. In embodiments, L7 is independently unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L7 is independently substituted or unsubstituted 2 to 12 membered heteroalkylene. In embodiments, L7 is independently substituted 2 to 12 membered heteroalkylene. In embodiments, L7 is independently oxo-substituted 2 to 12 membered heteroalkylene. In embodiments, L7 is independently unsubstituted 2 to 12 membered heteroalkylene. In embodiments, L7 is independently substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L7 is independently substituted 2 to 10 membered heteroalkylene. In embodiments, L7 is independently oxo-substituted 2 to 10 membered heteroalkylene. In embodiments, L7 is independently unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L7 is independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L7 is independently substituted 2 to 8 membered heteroalkylene. In embodiments, L7 is independently oxo-substituted 2 to 8 membered heteroalkylene. In embodiments, L7 is independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L7 is independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L7 is independently substituted 2 to 6 membered heteroalkylene. In embodiments, L7 is independently oxo-substituted 2 to 6 membered heteroalkylene. In embodiments, L7 is independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L7 is independently substituted or unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L7 is independently substituted 2 to 4 membered heteroalkylene. In embodiments, L7 is independently oxo-substituted 2 to 4 membered heteroalkylene. In embodiments, L7 is independently unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L7 is independently substituted or unsubstituted 2 to 20 membered heteroalkenylene. In embodiments, L7 is independently substituted 2 to 20 membered heteroalkenylene. In embodiments, L7 is independently oxo-substituted 2 to 20 membered heteroalkenylene. In embodiments, L7 is independently unsubstituted 2 to 20 membered heteroalkenylene. In embodiments, L7 is independently substituted or unsubstituted 2 to 12 membered heteroalkenylene. In embodiments, L7 is independently substituted 2 to 12 membered heteroalkenylene. In embodiments, L7 is independently oxo-substituted 2 to 12 membered heteroalkenylene. In embodiments, L7 is independently unsubstituted 2 to 12 membered heteroalkenylene. In embodiments, L7 is independently substituted or unsubstituted 2 to 10 membered heteroalkenylene. In embodiments, L7 is independently substituted 2 to 10 membered heteroalkenylene. In embodiments, L7 is independently oxo-substituted 2 to 10 membered heteroalkenylene. In embodiments, L7 is independently unsubstituted 2 to 10 membered heteroalkenylene. In embodiments, L7 is independently substituted or unsubstituted 2 to 8 membered heteroalkenylene. In embodiments, L7 is independently substituted 2 to 8 membered heteroalkenylene. In embodiments, L7 is independently oxo-substituted 2 to 8 membered heteroalkenylene. In embodiments, L7 is independently unsubstituted 2 to 8 membered heteroalkenylene. In embodiments, L7 is independently substituted or unsubstituted 2 to 6 membered heteroalkenylene. In embodiments, L7 is independently substituted 2 to 6 membered heteroalkenylene. In embodiments, L7 is independently oxo-substituted 2 to 6 membered heteroalkenylene. In embodiments, L7 is independently unsubstituted 2 to 6 membered heteroalkenylene. In embodiments, L7 is independently substituted or unsubstituted 2 to 4 membered heteroalkenylene. In embodiments, L7 is independently substituted 2 to 4 membered heteroalkenylene. In embodiments, L7 is independently oxo-substituted 2 to 4 membered heteroalkenylene. In embodiments, L7 is independently unsubstituted 2 to 4 membered heteroalkenylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)- or -O-L7-C(O)-NH-. In embodiments, L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, -L3-L4- is independently -O-L7-NH-C(O)- or -O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-; and L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L3-L4- is independently -O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-; and L7 is independently substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-; and L7 is independently hydroxy(OH)-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)- NH-and L7 is independently hydroxymethyl-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-; and L7 is independently unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently O-L7-C(O)-NH-; and L7 is independently substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-; and L7 is independently hydroxy(OH)-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH- and L7 is independently hydroxymethyl-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-; and L7 is independently unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-; and L7 is independently substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-; and L7 is independently hydroxy(OH)-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH- and L7 is independently hydroxymethyl-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-; and L7 is independently unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-; and L7 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-; and L7 is independently substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-; and L7 is independently hydroxy(OH)-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-; and L7 is independently hydroxymethyl-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-; and L7 is independently unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-; and L7 is independently substituted or unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-; and L7 is independently substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-; and L7 is independently hydroxy(OH)-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-; and L7 is independently hydroxymethyl-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-; and L7 is independently unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-; and L7 is independently substituted or unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-; and L7 is independently substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-; and L7 is independently hydroxy(OH)-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-; and L7 is independently hydroxymethyl-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-; and L7 is independently unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is independently , embodiments, -L3-L4- is independently . In embodiments, -L3-L4- is independently . In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-, -OP(O)(S)-O-L7-NH-C(O)-, -OPO2-O-L7-C(O)-NH-or -OP(O)(S)-O-L7-C(O)-NH-. In embodiments, L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)- or -OP(O)(S)-O-L7-NH-C(O)-; and L7 is independently substituted or unsubstituted alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7 is independently substituted or unsubstituted alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7 is independently substituted or unsubstituted alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH- or -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)- or -OPO2-O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)- or -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7 is independently substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7 is independently hydroxy(OH)-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7 is independently hydroxymethyl-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7 is independently unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently hydroxy(OH)-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently hydroxymethyl-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7 is independently substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7 is independently hydroxy(OH)-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7 is independently hydroxymethyl-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7 is independently unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently hydroxy(OH)-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently hydroxymethyl-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7 is independently substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7 is independently hydroxy(OH)-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7 is independently hydroxymethyl-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7 is independently unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently substituted or unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently hydroxy(OH)-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently hydroxymethyl-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7 is independently unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7 is independently substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7 is independently hydroxy(OH)-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7 is independently hydroxymethyl-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7 is independently unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7 is independently substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)2-O-L7-NH-C(O)-; and L7 is independently hydroxy(OH)-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7 is independently hydroxymethyl-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7 is independently unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7 is independently substituted or unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7 is independently substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7 is independently hydroxy(OH)-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7 is independently hydroxymethyl-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7 is independently unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7 is independently substituted or unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7 is independently substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7 is independently hydroxy(OH)-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7 is independently hydroxymethyl-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7 is independently unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7 is independently substituted or unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7 is independently substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7 is independently hydroxy(OH)-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7 is independently hydroxymethyl-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7 is independently unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7 is independently substituted or unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7 is independently substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7 is independently hydroxy(OH)-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7 is independently hydroxymethyl-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7 is independently unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is attached to a 3’ carbon of a nucleotide of the sense strand. In embodiments, -L3-L4- is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand. In embodiments, -L3-L4- is attached to a 3’ carbon of the antisense sense strand. In embodiments, -L3-L4- is attached to the 3’ carbon of the 3’ terminal nucleotide of the antisense sense strand. In embodiments, -L3-L4- is attached to a 5’ carbon of a nucleotide of the sense strand. In embodiments, -L3-L4- is attached to the 5’ carbon of the 5’ terminal nucleotide of the sense strand. In embodiments, -L3-L4- is attached to a 5’ carbon of a nucleotide of the antisense strand. In embodiments, -L3-L4- is attached to the 5’ carbon of the 5’ terminal nucleotide of the antisense strand. In embodiments, -L3-L4- is attached to a 2’ carbon of a nucleotide of the sense strand. In embodiments, -L3-L4- is attached to a 2’ carbon of a nucleotide of the antisense strand. [0001] In embodiments, -L3-L4- is attached to a nucleobase of the sense strand. In embodiments, -L3-L4- is attached to a nucleobase of the antisense strand. , . In embodiments, -L3-L4- is independently , , . embodiments, -L3-L4- is independently embodiments, -L3-L4- is independently , or . embodiments, -L3-L4- is independently
carbon of the 3’ terminal nucleotide of the sense strand. In embodiments, -L3-L4- is independently , , and is attached to the 3’ carbon of the 3’ terminal nucleotide of the antisense strand. In embodiments, -L3-L4- is independently that is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand. In embodiments, -L3-L4- is independently that is attached to the 3’ carbon of the 3’ terminal nucleotide of the antisense strand. In embodiments, -L3-L4- is independently , or that is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand. In embodiments, -L3-L4- is independently that is attached to the 3’ carbon of the 3’ terminal nucleotide of the antisense strand. In embodiments, an -L3-L4- is independently , and is attached to the 5’ carbon of the 5’ terminal nucleotide of the sense strand. In embodiments, an -L3-L4- is independently , and is attached to the 5’ carbon of the 5’ terminal nucleotide of the antisense strand. In embodiments, an -L3-L4- is independently that is attached to the 5’ carbon of the 5’ terminal nucleotide of the sense strand. In embodiments, an -L3-L4- is independentl y that is attached to the 5’ carbon of the 5’ terminal nucleotide of the antisense strand. In embodiments, an -L3-L4- is independently at is attached to 5’ carbon of the 5’ terminal nucleotide of the sense strand. In embodiments, an -L3-L4- is independently at is attached to the 5’ carbon of the 5’ terminal nucleotide of the antisense strand. In embodiments, an -L3-L4- is independently is attached to a nucleobase of the sense strand. In embodiments, an -L3-L4- is independently is attached to a nucleobase of the sense strand. In embodiments, an -L3-L4- is independently attached to a nucleobase of the antisense strand. In embodiments, -L3-L4- is independently
In embodiments, -L3-L4- is independently that is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand. In embodiments, -L3-L4- is independently that is attached to the 3’ carbon of the 3’ terminal nucleotide of the antisense strand. In embodiments, -L3-L4- is independently that is attached to the 5’ carbon of the 5’ terminal nucleotide of the sense strand. In embodiments, -L3-L4- is independently that is attached to the 5’ carbon of the 5’ terminal nucleotide of the antisense strand. In embodiments, -L3-L4- is independently that is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand. In embodiments, -L3-L4- is independently that is attached to the 3’ carbon of the 3’ terminal nucleotide of the antisense strand. In embodiments, -L3-L4- is independently that is attached to the 5’ carbon of the 5’ terminal nucleotide of the sense strand. In embodiments, -L3-L4- is independently that is attached to the 5’ carbon of the 5’ terminal nucleotide of the antisense strand. In embodiments, -L3-L4- is independently attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand. In embodiments, -L3-L4- is independently attached to the 3’ carbon of the 3’ terminal nucleotide of the antisense strand. In embodiments, -L3-L4- is independently and is attached to the 5’ carbon of the 5’ terminal nucleotide of the sense strand. In embodiments, -L3-L4- is independently and is attached to the 5’ carbon of the 5’ terminal nucleotide of the antisense strand. In embodiments, -L3-L4- is independently and is attached to a 2’ carbon of a nucleotide of the sense strand. In embodiments, -L3-L4- is independently and is attached to a 2’ carbon of a nucleotide of the antisense strand. In embodiments, -L3-L4- is independently and is attached to a 2’ carbon of a nucleotide of the sense strand. In embodiments, -L3-L4- is independently is attached to a 2’ carbon of a nucleotide of the antisense strand. In embodiments, -L3-L4- is independently is attached to a nucleobase of the sense strand. In embodiments, -L3-L4- is independently is attached to a nucleobase of the antisense strand. In embodiments, R3 is independently hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R3 is independently hydrogen. In embodiments, R3 is independently -NH2. In embodiments, R3 is independently -OH. In embodiments, R3 is independently -SH. In embodiments, R3 is independently -C(O)H. In embodiments, R3 is independently -C(O)NH2. In embodiments, R3 is independently -NHC(O)H. In embodiments, R3 is independently -NHC(O)OH. In embodiments, R3 is independently -NHC(O)NH2. In embodiments, R3 is independently -C(O)OH. In embodiments, R3 is independently -OC(O)H. In embodiments, R3 is independently -N3. In embodiments, R3 is independently substituted or unsubstituted alkyl (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R3 is independently substituted or unsubstituted C1-C20 alkyl. In embodiments, R3 is independently substituted C1-C20 alkyl. In embodiments, R3 is independently unsubstituted C1-C20 alkyl. In embodiments, R3 is independently substituted or unsubstituted C1-C12 alkyl. In embodiments, R3 is independently substituted C1-C12 alkyl. In embodiments, R3 is independently unsubstituted C1-C12 alkyl. In embodiments, R3 is independently substituted or unsubstituted C1-C8 alkyl. In embodiments, R3 is independently substituted C1-C8 alkyl. In embodiments, R3 is independently unsubstituted C1-C8 alkyl. In embodiments, R3 is independently substituted or unsubstituted C1-C6 alkyl. In embodiments, R3 is independently substituted C1-C6 alkyl. In embodiments, R3 is independently unsubstituted C1-C6 alkyl. In embodiments, R3 is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R3 is independently substituted C1-C4 alkyl. In embodiments, R3 is independently unsubstituted C1-C4 alkyl. In embodiments, R3 is independently substituted or unsubstituted ethyl. In embodiments, R3 is independently substituted ethyl. In embodiments, R3 is independently unsubstituted ethyl. In embodiments, R3 is independently substituted or unsubstituted methyl. In embodiments, R3 is independently substituted methyl. In embodiments, R3 is independently unsubstituted methyl. In embodiments, L6 is independently -NHC(O)-. In embodiments, L6 is independently -C(O)NH-. In embodiments, L6 is independently substituted or unsubstituted alkylene. In embodiments, L6 is independently substituted or unsubstituted heteroalkylene. In embodiments, L6 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6 is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6 is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6 is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L6 is independently substituted C1-C20 alkylene. In embodiments, L6 is independently unsubstituted C1-C20 alkylene. In embodiments, L6 is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L6 is independently substituted C1-C12 alkylene. In embodiments, L6 is independently unsubstituted C1-C12 alkylene. In embodiments, L6 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L6 is independently substituted C1-C8 alkylene. In embodiments, L6 is independently unsubstituted C1-C8 alkylene. In embodiments, L6 is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L6 is independently substituted C1-C6 alkylene. In embodiments, L6 is independently unsubstituted C1-C6 alkylene. In embodiments, L6 is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L6 is independently substituted C1-C4 alkylene. In embodiments, L6 is independently unsubstituted C1-C4 alkylene. In embodiments, L6 is independently substituted or unsubstituted ethylene. In embodiments, L6 is independently substituted ethylene. In embodiments, L6 is independently unsubstituted ethylene. In embodiments, L6 is independently substituted or unsubstituted methylene. In embodiments, L6 is independently substituted methylene. In embodiments, L6 is independently unsubstituted methylene. In embodiments, L6 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L6 is independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L6 is independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L6 is independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L6 is independently substituted 2 to 20 membered heteroalkylene. In embodiments, L6 is independently unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L6 is independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L6 is independently substituted 2 to 8 membered heteroalkylene. In embodiments, L6 is independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L6 is independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L6 is independently substituted 2 to 6 membered heteroalkylene. In embodiments, L6 is independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L6 is independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L6 is independently substituted 4 to 6 membered heteroalkylene. In embodiments, L6 is independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L6 is independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L6 is independently substituted 2 to 3 membered heteroalkylene. In embodiments, L6 is independently unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L6 is independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L6 is independently substituted 4 to 5 membered heteroalkylene. In embodiments, L6 is independently unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L6A is independently a bond or unsubstituted alkylene; L6B is independently a bond, -NHC(O)-, or unsubstituted arylene; L6C is independently a bond, unsubstituted alkylene, or unsubstituted arylene; L6D is independently a bond or unsubstituted alkylene; and L6E is independently a bond or -NHC(O)-. In embodiments, L6A is independently a bond or unsubstituted alkylene. In embodiments, L6B is independently a bond, -NHC(O)-, or unsubstituted arylene. In embodiments, L6C is independently a bond, unsubstituted alkylene, or unsubstituted arylene. In embodiments, L6D is independently a bond or unsubstituted alkylene. In embodiments, L6E is independently a bond or -NHC(O)-. In embodiments, L6A is independently a bond or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6A is independently unsubstituted C1-C20 alkylene. In embodiments, L6A is independently unsubstituted C1-C12 alkylene. In embodiments, L6A is independently unsubstituted C1-C8 alkylene. In embodiments, L6A is independently unsubstituted C1-C6 alkylene. In embodiments, L6A is independently unsubstituted C1-C4 alkylene. In embodiments, L6A is independently unsubstituted ethylene. In embodiments, L6A is independently unsubstituted methylene. In embodiments, L6A is independently a bond. In embodiments, L6B is independently a bond. In embodiments, L6B is independently -NHC(O)-. In embodiments, L6B is independently unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L6B is independently unsubstituted C6-C12 arylene. In embodiments, L6B is independently unsubstituted C6-C10 arylene. In embodiments, L6B is independently unsubstituted phenylene. In embodiments, L6B is independently unsubstituted naphthylene. In embodiments, L6B is independently unsubstituted biphenylene. In embodiments, L6C is independently a bond or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6C is independently unsubstituted C1-C20 alkylene. In embodiments, L6C is independently unsubstituted C1-C12 alkylene. In embodiments, L6C is independently unsubstituted C1-C8 alkylene. In embodiments, L6C is independently unsubstituted C2-C8 alkynylene. In embodiments, L6C is independently unsubstituted C1-C6 alkylene. In embodiments, L6C is independently unsubstituted C1-C4 alkylene. In embodiments, L6C is independently unsubstituted ethylene. In embodiments, L6C is independently unsubstituted methylene. In embodiments, L6C is independently a bond or unsubstituted alkynylene (e.g., C2-C20, C2-C12, C2-C8, C2-C6, C2-C4, or C2-C2). In embodiments, L6C is independently unsubstituted C2-C20 alkynylene. In embodiments, L6C is independently unsubstituted C2-C12 alkynylene. In embodiments, L6C is independently unsubstituted C2-C8 alkynylene. In embodiments, L6C is independently unsubstituted C2-C6 alkynylene. In embodiments, L6C is independently unsubstituted C2-C4 alkynylene. In embodiments, L6C is independently unsubstituted ethynylene. In embodiments, L6C is independently unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L6C is independently unsubstituted C6-C12 arylene. In embodiments, L6C is independently unsubstituted C6-C10 arylene. In embodiments, L6C is independently unsubstituted phenylene. In embodiments, L6C is independently unsubstituted naphthylene. In embodiments, L6C is independently a bond. In embodiments, L6D is independently a bond or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6D is independently unsubstituted C1-C20 alkylene. In embodiments, L6D is independently unsubstituted C1-C12 alkylene. In embodiments, L6A is independently unsubstituted C1-C8 alkylene. In embodiments, L6D is independently unsubstituted C1-C6 alkylene. In embodiments, L6D is independently unsubstituted C1-C4 alkylene. In embodiments, L6D is independently unsubstituted ethylene. In embodiments, L6D is independently unsubstituted methylene. In embodiments, L6D is independently a bond. In embodiments, L6E is independently a bond. In embodiments, L6E is independently -NHC(O)-. In embodiments, L6A is independently a bond or unsubstituted C1-C8 alkylene. In embodiments, L6B is independently a bond, -NHC(O)-, or unsubstituted phenylene. In embodiments, L6C is independently a bond, unsubstituted C2-C8 alkynylene, or unsubstituted phenylene. In embodiments, L6D is independently a bond or unsubstituted C1-C8 alkylene. In embodiments, L6E is independently a bond or -NHC(O)-. In embodiments, L6 is independently a bond, , independently a bond. In embodiments, L6 is independently . embodiments, L6 is independently . embodiments, L6 is independently . embodiments, L6 is independently . In embodiments, L6 is independently . In embodiments, L5 is independently -NHC(O)-. In embodiments, L5 is independently -C(O)NH-. In embodiments, L5 is independently substituted or unsubstituted alkylene. In embodiments, L5 is independently substituted or unsubstituted heteroalkylene. In embodiments, L5 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5 is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5 is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5 is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L5 is independently substituted C1-C20 alkylene. In embodiments, L5 is independently unsubstituted C1-C20 alkylene. In embodiments, L5 is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L5 is independently substituted C1-C12 alkylene. In embodiments, L5 is independently unsubstituted C1-C12 alkylene. In embodiments, L5 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L5 is independently substituted C1-C8 alkylene. In embodiments, L5 is independently unsubstituted C1-C8 alkylene. In embodiments, L5 is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L5 is independently substituted C1-C6 alkylene. In embodiments, L5 is independently unsubstituted C1-C6 alkylene. In embodiments, L5 is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L5 is independently substituted C1-C4 alkylene. In embodiments, L5 is independently unsubstituted C1-C4 alkylene. In embodiments, L5 is independently substituted or unsubstituted ethylene. In embodiments, L5 is independently substituted ethylene. In embodiments, L5 is independently unsubstituted ethylene. In embodiments, L5 is independently substituted or unsubstituted methylene. In embodiments, L5 is independently substituted methylene. In embodiments, L5 is independently unsubstituted methylene. In embodiments, L5 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L5 is independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L5 is independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L5 is independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L5 is independently substituted 2 to 20 membered heteroalkylene. In embodiments, L5 is independently unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L5 is independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L5 is independently substituted 2 to 8 membered heteroalkylene. In embodiments, L5 is independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L5 is independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L5 is independently substituted 2 to 6 membered heteroalkylene. In embodiments, L5 is independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L5 is independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L5 is independently substituted 4 to 6 membered heteroalkylene. In embodiments, L5 is independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L5 is independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L5 is independently substituted 2 to 3 membered heteroalkylene. In embodiments, L5 is independently unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L5 is independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L5 is independently substituted 4 to 5 membered heteroalkylene. In embodiments, L5 is independently unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L5A is independently a bond or unsubstituted alkylene; L5B is independently a bond, -NHC(O)-, or unsubstituted arylene; L5C is independently a bond, unsubstituted alkylene, or unsubstituted arylene; L5D is independently a bond or unsubstituted alkylene; and L5E is independently a bond or -NHC(O)-. In embodiments, L5A is independently a bond or unsubstituted alkylene. In embodiments, L5B is independently a bond, -NHC(O)-, or unsubstituted arylene. In embodiments, L5C is independently a bond, unsubstituted alkylene, or unsubstituted arylene. In embodiments, L5D is independently a bond or unsubstituted alkylene. In embodiments, L5E is independently a bond or -NHC(O)-. In embodiments, L5A is independently a bond or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5A is independently unsubstituted C1-C20 alkylene. In embodiments, L5A is independently unsubstituted C1-C12 alkylene. In embodiments, L5A is independently unsubstituted C1-C8 alkylene. In embodiments, L5A is independently unsubstituted C1-C6 alkylene. In embodiments, L5A is independently unsubstituted C1-C4 alkylene. In embodiments, L5A is independently unsubstituted ethylene. In embodiments, L5A is independently unsubstituted methylene. In embodiments, L5A is independently a bond. In embodiments, L5B is independently a bond. In embodiments, L5B is independently -NHC(O)-. In embodiments, L5B is independently unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L5B is independently unsubstituted C6-C12 arylene. In embodiments, L5B is independently unsubstituted C6-C10 arylene. In embodiments, L5B is independently unsubstituted phenylene. In embodiments, L5B is independently unsubstituted naphthylene. In embodiments, L5C is independently a bond or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5C is independently unsubstituted C1-C20 alkylene. In embodiments, L5C is independently unsubstituted C1-C12 alkylene. In embodiments, L5C is independently unsubstituted C1-C8 alkylene. In embodiments, L5C is independently unsubstituted C2-C8 alkynylene. In embodiments, L5C is independently unsubstituted C1-C6 alkylene. In embodiments, L5C is independently unsubstituted C1-C4 alkylene. In embodiments, L5C is independently unsubstituted ethylene. In embodiments, L5C is independently unsubstituted methylene. In embodiments, L5C is independently a bond or unsubstituted alkynylene (e.g., C2-C20, C2-C12, C2-C8, C2-C6, C2-C4, or C2-C2). In embodiments, L5C is independently unsubstituted C2-C20 alkynylene. In embodiments, L5C is independently unsubstituted C2-C12 alkynylene. In embodiments, L5C is independently unsubstituted C2-C8 alkynylene. In embodiments, L5C is independently unsubstituted C2-C6 alkynylene. In embodiments, L5C is independently unsubstituted C2-C4 alkynylene. In embodiments, L5C is independently unsubstituted ethynylene. In embodiments, L5C is independently unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L5C is independently unsubstituted C6-C12 arylene. In embodiments, L5C is independently unsubstituted C6-C10 arylene. In embodiments, L5C is independently unsubstituted phenylene. In embodiments, L5C is independently unsubstituted naphthylene. In embodiments, L5C is independently a bond. In embodiments, L5D is independently a bond or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5D is independently unsubstituted C1-C20 alkylene. In embodiments, L5D is independently unsubstituted C1-C12 alkylene. In embodiments, L5A is independently unsubstituted C1-C8 alkylene. In embodiments, L5D is independently unsubstituted C1-C6 alkylene. In embodiments, L5D is independently unsubstituted C1-C4 alkylene. In embodiments, L5D is independently unsubstituted ethylene. In embodiments, L5D is independently unsubstituted methylene. In embodiments, L5D is independently a bond. In embodiments, L5E is independently a bond. In embodiments, L5E is independently -NHC(O)-. In embodiments, L5A is independently a bond or unsubstituted C1-C8 alkylene. In embodiments, L5B is independently a bond, -NHC(O)-, or unsubstituted phenylene. In embodiments, L5C is independently a bond, unsubstituted C2-C8 alkynylene, or unsubstituted phenylene. In embodiments, L5D is independently a bond or unsubstituted C1-C8 alkylene. In embodiments, L5E is independently a bond or -NHC(O)-. In embodiments, L5 is independently a bond, , In e 5 mbodiments, L is independently a bond. In embodiments, L5 is independently . In embodiments, L5 is independently . In embodiments, L5 is independently . In embodiments, L5 is independently In embodiments, L5 is independently In embodiments, R1 is unsubstituted alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R1 is unsubstituted unbranched alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R1 is unsubstituted unbranched saturated alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R1 is unsubstituted unbranched unsaturated alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R1 is unsubstituted C1-C17 alkyl. In embodiments, R1 is unsubstituted C11-C17 alkyl. In embodiments, R1 is unsubstituted C13-C17 alkyl. In embodiments, R1 is unsubstituted C14-C15 alkyl. In embodiments, R1 is unsubstituted C15 alkyl. In embodiments, R1 is unsubstituted C14 alkyl. In embodiments, R1 is unsubstituted unbranched C1-C17 alkyl. In embodiments, R1 is unsubstituted unbranched C11-C17 alkyl. In embodiments, R1 is unsubstituted unbranched C13-C17 alkyl. In embodiments, R1 is unsubstituted unbranched C14-C15 alkyl. In embodiments, R1 is unsubstituted unbranched C14 alkyl. In embodiments, R1 is unsubstituted unbranched C15 alkyl. In embodiments, R1 is unsubstituted unbranched saturated C1-C17 alkyl. In embodiments, R1 is unsubstituted unbranched saturated C11-C17 alkyl. In embodiments, R1 is unsubstituted unbranched saturated C13-C17 alkyl. In embodiments, R1 is unsubstituted unbranched saturated C14-C15 alkyl. In embodiments, R1 is unsubstituted unbranched saturated C14 alkyl. In embodiments, R1 is unsubstituted unbranched saturated C15 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated C1-C17 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated C11-C17 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated C13-C17 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated C14-C15 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated C14 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated C15 alkyl. In embodiments, R2 is unsubstituted alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R2 is unsubstituted unbranched alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R2 is unsubstituted unbranched saturated alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R2 is unsubstituted unbranched unsaturated alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R2 is unsubstituted C1-C17 alkyl. In embodiments, R2 is unsubstituted C11-C17 alkyl. In embodiments, R2 is unsubstituted C13-C17 alkyl. In embodiments, R2 is unsubstituted C14-C15 alkyl. In embodiments, R2 is unsubstituted C14 alkyl. In embodiments, R2 is unsubstituted C15 alkyl. In embodiments, R2 is unsubstituted unbranched C1-C17 alkyl. In embodiments, R2 is unsubstituted unbranched C11-C17 alkyl. In embodiments, R2 is unsubstituted unbranched C13-C17 alkyl. In embodiments, R2 is unsubstituted unbranched C14-C15 alkyl. In embodiments, R2 is unsubstituted unbranched C14 alkyl. In embodiments, R2 is unsubstituted unbranched C15 alkyl. In embodiments, R2 is unsubstituted unbranched saturated C1-C17 alkyl. In embodiments, R2 is unsubstituted unbranched saturated C11-C17 alkyl. In embodiments, R2 is unsubstituted unbranched saturated C13-C17 alkyl. In embodiments, R2 is unsubstituted unbranched saturated C14-C15 alkyl. In embodiments, R2 is unsubstituted unbranched saturated C14 alkyl. In embodiments, R2 is unsubstituted unbranched saturated C15 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated C1-C17 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated C11-C17 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated C13-C17 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated C14-C15 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated C14 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated C15 alkyl. In embodiments, at least one of R1 and R2 is unsubstituted C1-C19 alkyl. In embodiments, at least one of R1 and R2 is unsubstituted C9-C19 alkyl. In embodiments, at least one of R1 and R2 is unsubstituted C11-C19 alkyl. In embodiments, at least one of R1 and R2 is unsubstituted C13-C19 alkyl. In embodiments, R1 is unsubstituted C1-C19 alkyl. In embodiments, R1 is unsubstituted C9-C19 alkyl. In embodiments, R1 is unsubstituted C11-C19 alkyl. In embodiments, R1 is unsubstituted C13-C19 alkyl. In embodiments, R1 is unsubstituted unbranched C1-C19 alkyl. In embodiments, R1 is unsubstituted unbranched C9-C19 alkyl. In embodiments, R1 is unsubstituted unbranched C11-C19 alkyl. In embodiments, R1 is unsubstituted unbranched C13-C19 alkyl. In embodiments, R1 is unsubstituted unbranched saturated C1-C19 alkyl. In embodiments, R1 is unsubstituted unbranched saturated C9-C19 alkyl. In embodiments, R1 is unsubstituted unbranched saturated C11-C19 alkyl. In embodiments, R1 is unsubstituted unbranched saturated C13-C19 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated C1-C19 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated C9-C19 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated C11-C19 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated C13-C19 alkyl. In embodiments, R2 is unsubstituted C1-C19 alkyl. In embodiments, R2 is unsubstituted C9-C19 alkyl. In embodiments, R2 is unsubstituted C11-C19 alkyl. In embodiments, R2 is unsubstituted C13-C19 alkyl. In embodiments, R2 is unsubstituted unbranched C1-C19 alkyl. In embodiments, R2 is unsubstituted unbranched C9-C19 alkyl. In embodiments, R2 is unsubstituted unbranched C11-C19 alkyl. In embodiments, R2 is unsubstituted unbranched C13-C19 alkyl. In embodiments, R2 is unsubstituted unbranched saturated C1-C19 alkyl. In embodiments, R2 is unsubstituted unbranched saturated C9-C19 alkyl. In embodiments, R2 is unsubstituted unbranched saturated C11-C19 alkyl. In embodiments, R2 is unsubstituted unbranched saturated C13-C19 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated C1-C19 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated C9-C19 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated C11-C19 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated C13-C19 alkyl. L3 is independently a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, -C(O)N(R24)-, -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O-P(S)(NR23R24)-N-, -O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-, -S-S-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L3 is independently a bond, a -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, -C(O)N(R24)-, -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O-P(S)(NR23R24)-N-, -O-P(O)(NR23(e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L3 is independently a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, -C(O)N(R24)-, -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O-P(S)(NR23R24)-N-, -O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-,-S-S-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, when L3 is substituted, L3 is substituted with a substituent group. In embodiments, when L3 is substituted, L3 is substituted with a size-limited substituent group. In embodiments, when L3 is substituted, L3 is substituted with a lower substituent group. L4 is independently a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, -C(O)N(R24)-, -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O-P(S)(NR23R24)-N-, -O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-, -S-S-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L4 is a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, -C(O)N(R24)-, -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O-P(S)(NR23R24)-N-, -O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-,-S-S-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L4 is a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, -C(O)N(R24)-, -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O-P(S)(NR23R24)-N-, -O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-,-S-S-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, when L4 is substituted, L4 is substituted with a substituent group. In embodiments, when L4 is substituted, L4 is substituted with a size-limited substituent group. In embodiments, when L4 is substituted, L4 is substituted with a lower substituent group. R23 is independently hydrogen or unsubstituted alkyl (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R23 is independently hydrogen. In embodiments, R23 is independently unsubstituted C1-C23 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C12 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C10 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C8 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C2 alkyl. R24 is independently hydrogen or unsubstituted alkyl (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R24 is independently hydrogen. In embodiments, R24 is independently unsubstituted C1-C23 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C12 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C10 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C8 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C2 alkyl. R25 is independently hydrogen or unsubstituted alkyl (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R25 is independently hydrogen. In embodiments, R25 is independently unsubstituted C1-C23 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C12 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C10 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C8 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C2 alkyl. L5A is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L5A is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L5A is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, when L5A is substituted, L5A is substituted with a substituent group. In embodiments, when L5A is substituted, L5A is substituted with a size-limited substituent group. In embodiments, when L5A is substituted, L5A is substituted with a lower substituent group. L5B is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L5B is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L5B is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, –C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, when L5B is substituted, L5B is substituted with a substituent group. In embodiments, when L5B is substituted, L5B is substituted with a size-limited substituent group. In embodiments, when L5B is substituted, L5B is substituted with a lower substituent group. L5C is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L5C is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L5C is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, when L5C is substituted, L5C is substituted with a substituent group. In embodiments, when L5C is substituted, L5C is substituted with a size-limited substituent group. In embodiments, when L5C is substituted, L5C is substituted with a lower substituent group. L5D is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L5D is a bond, -NH-, -O-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L5D is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, when L5D is substituted, L5D is substituted with a substituent group. In embodiments, when L5D is substituted, L5D is substituted with a size-limited substituent group. In embodiments, when L5D is substituted, L5D is substituted with a lower substituent group. L5E is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L5E is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L5E is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, when L5E is substituted, L5E is substituted with a substituent group. In embodiments, when L5E is substituted, L5E is substituted with a size-limited substituent group. In embodiments, when L5E is substituted, L5E is substituted with a lower substituent group. L6 is independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L6 is independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L6 is independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, when L6 is substituted, L6 is substituted with a substituent group. In embodiments, when L6 is substituted, L6 is substituted with a size-limited substituent group. In embodiments, when L6 is substituted, L6 is substituted with a lower substituent group. L6A is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L6A is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L6A is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, when L6A is substituted, L6A is substituted with a substituent group. In embodiments, when L6A is substituted, L6A is substituted with a size-limited substituent group. In embodiments, when L6A is substituted, L6A is substituted with a lower substituent group. L6B is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L6B is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L6B is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, when L6B is substituted, L6B is substituted with a substituent group. In embodiments, when L6B is substituted, L6B is substituted with a size-limited substituent group. In embodiments, when L6B is substituted, L6B is substituted with a lower substituent group. L6C is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L6C is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L6C is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, when L6C is substituted, L6C is substituted with a substituent group. In embodiments, when L6C is substituted, L6C is substituted with a size-limited substituent group. In embodiments, when L6C is substituted, L6C is substituted with a lower substituent group. L6D is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L6D is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L6D is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, when L6D is substituted, L6D is substituted with a substituent group. In embodiments, when L6D is substituted, L6D is substituted with a size-limited substituent group. In embodiments, when L6D is substituted, L6D is substituted with a lower substituent group. L6E is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L6E is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) arylene (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L6E is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkylene (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, when L6E is substituted, L6E is substituted with a substituent group. In embodiments, when L6E is substituted, L6E is substituted with a size-limited substituent group. In embodiments, when L6E is substituted, L6E is substituted with a lower substituent group. In embodiments, L7 is independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7 is independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7 is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7 is independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7 is independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7 is independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7 is independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7 is independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7 is independently unsubstituted heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, when L7 is substituted, L7 is substituted with a substituent group. In embodiments, when L7 is substituted, L7 is substituted with a size-limited substituent group. In embodiments, when L7 is substituted, L7 is substituted with a lower substituent group. In embodiments, R1 is unsubstituted alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R1 is unsubstituted C1-C25 alkyl. In embodiments, R1 is unsubstituted C1-C20 alkyl. In embodiments, R1 is unsubstituted C1-C12 alkyl. In embodiments, R1 is unsubstituted C1-C8 alkyl. In embodiments, R1 is unsubstituted C1-C6 alkyl. In embodiments, R1 is unsubstituted C1-C4 alkyl. In embodiments, R1 is unsubstituted C1-C2 alkyl. In embodiments, R1 is unsubstituted branched alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R1 is unsubstituted branched C1-C25 alkyl. In embodiments, R1 is unsubstituted branched C1-C20 alkyl. In embodiments, R1 is unsubstituted branched C1-C12 alkyl. In embodiments, R1 is unsubstituted branched C1-C8 alkyl. In embodiments, R1 is unsubstituted branched C1-C6 alkyl. In embodiments, R1 is unsubstituted branched C1-C4 alkyl. In embodiments, R1 is unsubstituted branched C1-C2 alkyl. In embodiments, R1 is unsubstituted unbranched alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R1 is unsubstituted unbranched C1-C25 alkyl. In embodiments, R1 is unsubstituted unbranched C1-C20 alkyl. In embodiments, R1 is unsubstituted unbranched C1-C12 alkyl. In embodiments, R1 is unsubstituted unbranched C1-C8 alkyl. In embodiments, R1 is unsubstituted unbranched C1-C6 alkyl. In embodiments, R1 is unsubstituted unbranched C1-C4 alkyl. In embodiments, R1 is unsubstituted unbranched C1-C2 alkyl. In embodiments, R1 is unsubstituted branched saturated alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R1 is unsubstituted branched saturated C1-C25 alkyl. In embodiments, R1 is unsubstituted branched saturated C1-C20 alkyl. In embodiments, R1 is unsubstituted branched saturated C1-C12 alkyl. In embodiments, R1 is unsubstituted branched saturated C1-C8 alkyl. In embodiments, R1 is unsubstituted branched saturated C1-C6 alkyl. In embodiments, R1 is unsubstituted branched saturated C1-C4 alkyl. In embodiments, R1 is unsubstituted branched saturated C1-C2 alkyl. In embodiments, R1 is unsubstituted branched unsaturated alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R1 is unsubstituted branched unsaturated C1-C25 alkyl. In embodiments, R1 is unsubstituted branched unsaturated C1-C20 alkyl. In embodiments, R1 is unsubstituted branched unsaturated C1-C12 alkyl. In embodiments, R1 is unsubstituted branched unsaturated C1-C8 alkyl. In embodiments, R1 is unsubstituted branched unsaturated C1-C6 alkyl. In embodiments, R1 is unsubstituted branched unsaturated C1-C4 alkyl. In embodiments, R1 is unsubstituted branched saturated C1-C2 alkyl. In embodiments, R1 is unsubstituted unbranched saturated alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R1 is unsubstituted unbranched saturated C1-C25 alkyl. In embodiments, R1 is unsubstituted unbranched saturated C1-C20 alkyl. In embodiments, R1 is unsubstituted unbranched saturated C1-C12 alkyl. In embodiments, R1 is unsubstituted unbranched saturated C1-C8 alkyl. In embodiments, R1 is unsubstituted unbranched saturated C1-C6 alkyl. In embodiments, R1 is unsubstituted unbranched saturated C1-C4 alkyl. In embodiments, R1 is unsubstituted unbranched saturated C1-C2 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R1 is unsubstituted unbranched unsaturated C1-C25 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated C1-C20 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated C1-C12 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated C1-C8 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated C1-C6 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated C1-C4 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated C1-C2 alkyl. In embodiments, R1 is unsubstituted C9-C19 alkyl. In embodiments, R1 is unsubstituted branched C9-C19 alkyl. In embodiments, R1 is unsubstituted unbranched C9-C19 alkyl. In embodiments, R1 is unsubstituted branched saturated C9-C19 alkyl. In embodiments, R1 is unsubstituted branched unsaturated C9-C19 alkyl. In embodiments, R1 is unsubstituted unbranched saturated C9-C19 alkyl. In embodiments, R1 is unsubstituted unbranched unsaturated C9-C19 alkyl. In embodiments, R2 is unsubstituted alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R2 is unsubstituted C1-C25 alkyl. In embodiments, R2 is unsubstituted C1-C20 alkyl. In embodiments, R2 is unsubstituted C1-C12 alkyl. In embodiments, R2 is unsubstituted C1-C8 alkyl. In embodiments, R2 is unsubstituted C1-C6 alkyl. In embodiments, R2 is unsubstituted C1-C4 alkyl. In embodiments, R2 is unsubstituted C1-C2 alkyl. In embodiments, R2 is unsubstituted branched alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R2 is unsubstituted branched C1-C25 alkyl. In embodiments, R2 is unsubstituted branched C1-C20 alkyl. In embodiments, R2 is unsubstituted branched C1-C12 alkyl. In embodiments, R2 is unsubstituted branched C1-C8 alkyl. In embodiments, R2 is unsubstituted branched C1-C6 alkyl. In embodiments, R2 is unsubstituted branched C1-C4 alkyl. In embodiments, R2 is unsubstituted branched C1-C2 alkyl. In embodiments, R2 is unsubstituted unbranched alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R2 is unsubstituted unbranched C1-C25 alkyl. In embodiments, R2 is unsubstituted unbranched C1-C20 alkyl. In embodiments, R2 is unsubstituted unbranched C1-C12 alkyl. In embodiments, R2 is unsubstituted unbranched C1-C8 alkyl. In embodiments, R2 is unsubstituted unbranched C1-C6 alkyl. In embodiments, R2 is unsubstituted unbranched C1-C4 alkyl. In embodiments, R2 is unsubstituted unbranched C1-C2 alkyl. In embodiments, R2 is unsubstituted branched saturated alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R2 is unsubstituted branched saturated C1-C25 alkyl. In embodiments, R2 is unsubstituted branched saturated C1-C20 alkyl. In embodiments, R2 is unsubstituted branched saturated C1-C12 alkyl. In embodiments, R2 is unsubstituted branched saturated C1-C8 alkyl. In embodiments, R2 is unsubstituted branched saturated C1-C6 alkyl. In embodiments, R2 is unsubstituted branched saturated C1-C4 alkyl. In embodiments, R2 is unsubstituted branched saturated C1-C2 alkyl. In embodiments, R2 is unsubstituted branched unsaturated alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R2 is unsubstituted branched unsaturated C1-C25 alkyl. In embodiments, R2 is unsubstituted branched unsaturated C1-C20 alkyl. In embodiments, R2 is unsubstituted branched unsaturated C1-C12 alkyl. In embodiments, R2 is unsubstituted branched unsaturated C1-C8 alkyl. In embodiments, R2 is unsubstituted branched unsaturated C1-C6 alkyl. In embodiments, R2 is unsubstituted branched unsaturated C1-C4 alkyl. In embodiments, R2 is unsubstituted branched saturated C1-C2 alkyl. In embodiments, R2 is unsubstituted unbranched saturated alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R2 is unsubstituted unbranched saturated C1-C25 alkyl. In embodiments, R2 is unsubstituted unbranched saturated C1-C20 alkyl. In embodiments, R2 is unsubstituted unbranched saturated C1-C12 alkyl. In embodiments, R2 is unsubstituted unbranched saturated C1-C8 alkyl. In embodiments, R2 is unsubstituted unbranched saturated C1-C6 alkyl. In embodiments, R2 is unsubstituted unbranched saturated C1-C4 alkyl. In embodiments, R2 is unsubstituted unbranched saturated C1-C2 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated alkyl (e.g., C1-C25, C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R2 is unsubstituted unbranched unsaturated C1-C25 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated C1-C20 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated C1-C12 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated C1-C8 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated C1-C6 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated C1-C4 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated C1-C2 alkyl. In embodiments, R2 is unsubstituted C9-C19 alkyl. In embodiments, R2 is unsubstituted branched C9-C19 alkyl. In embodiments, R2 is unsubstituted unbranched C9-C19 alkyl. In embodiments, R2 is unsubstituted branched saturated C9-C19 alkyl. In embodiments, R2 is unsubstituted branched unsaturated C9-C19 alkyl. In embodiments, R2 is unsubstituted unbranched saturated C9-C19 alkyl. In embodiments, R2 is unsubstituted unbranched unsaturated C9-C19 alkyl. In embodiments, R3 is hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, -N3, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R3 is hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, -N3, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) alkyl (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) cycloalkyl (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) aryl (e.g., C6-C12, C6-C10, or phenyl), or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R3 is hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C (O)OH, -OC(O)H, –N3, unsubstituted alkyl (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C10, C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, when R3 is substituted, R3 is substituted with a substituent group. In embodiments, when R3 is substituted, R3 is substituted with a size-limited substituent group. In embodiments, when R3 is substituted, R3 is substituted with a lower substituent group (e.g., oxo). In embodiments, the uptake motif is represented by the structure: The uptake motif is attached to the remainder of the compunds provided here through the –L3-L4- moiety as set forth in Formula (I) above. The wavy line represents attachment to the L4 linker in Formula (I). L3, L4, R1, R2, R3, L5, and L6 in Formula (I-a) are as described in Formula (I), including embodiments thereof. In embodiments, the compound comprises one or more uptake motifs having a structure shown in Table 3 below. In embodiments, the compound comprises a DTx-01-01 motif in Table 3. In embodiments, the compound comprises a DTx-01-03 motif 1 of Table 3. In embodiments, the compound comprises a DTx-01-06 motif in Table 3. In embodiments, the compound comprises a DTx-01-08 motif in Table 3. In embodiments, the compound comprises a DTx-01-11 motif in Table 3. In embodiments, the compound comprises a DTx-01-13 motif in Table 3. In embodiments, the compound comprises a DTx-01-30 motif in Table 3. In embodiments, the compound comprises a DTx-01-31 motif in Table 3. In embodiments, the compound comprises a DTx-01-32 motif in Table 3. In embodiments, the compound comprises a DTx-01-33 motif in Table 3. In embodiments, the compound comprises a DTx-01-34 motif in Table 3. In embodiments, the compound comprises a DTx-01-35 motif in Table 3. In embodiments, the compound comprises a DTx-01-36 motif in Table 3. In embodiments, the compound comprises a DTx-01-39 motif in Table 3. In embodiments, the compound comprises a DTx-01-43 motif in Table 3. In embodiments, the compound comprises a DTx-01-44 motif in Table 3. In embodiments, the compound comprises a DTx-01-45 motif in Table 3. In embodiments, the compound comprises a DTx-01-46 motif in Table 3. In embodiments, the compound comprises a DTx-01-50 motif in Table 3. In embodiments, the compound comprises a DTx-01-51 motif in Table 3. In embodiments, the compound comprises a DTx-01-52 motif in Table 3. In embodiments, the compound comprises a DTx-01-53 motif in Table 3. In embodiments, the compound comprises a DTx-01-54 motif in Table 3. In embodiments, the compound comprises a DTx-01-55 motif in Table 3. In embodiments, the compound comprises a DTx-03-06 motif in Table 3. In embodiments, the compound comprises a DTx-03-50 motif in Table 3. In embodiments, the compound comprises a DTx-03-51 motif in Table 3. In embodiments, the compound comprises a DTx-03-52 motif in Table 3. In embodiments, the compound comprises a DTx-03-53 motif in Table 3. In embodiments, the compound comprises a DTx-03-54 motif in Table 3. In embodiments, the compound comprises a DTx-03-55 motif in Table 3. In embodiments, the compound comprises a DTx-04-01 motif in Table 3. In embodiments, the compound comprises a DTx-05-01 motif in Table 3. In embodiments, the compound comprises a DTx-06-06 motif in Table 3. In embodiments, the compound comprises a DTx-06-50 motif in Table 3. In embodiments, the compound comprises a DTx-06-51 motif in Table 3. In embodiments, the compound comprises a DTx-06-52 motif in Table 3. In embodiments, the compound comprises a DTx-06-53 motif in Table 3. In embodiments, the compound comprises a DTx-06-54 motif in Table 3. In embodiments, the compound comprises a DTx-06-55 motif in Table 3. In embodiments, the compound comprises a DTx-08-01 motif in Table 3. In embodiments, the compound comprises a DTx-09-01 motif in Table 3. In embodiments, the compound comprises a DTx-10-01 motif in Table 3. In embodiments, the compound comprises a DTx-11-01 motif in Table 3. In embodiments, the compound comprises a DTx-01-60 motif in Table 3. In embodiments, the compound comprises a DTx-01-61 motif in Table 3. In embodiments, the compound comprises a DTx-01-62 motif in Table 3. In embodiments, the compound comprises a DTx-01-63 motif in Table 3. In embodiments, the compound comprises a DTx-01-64 motif in Table 3. In embodiments, the compound comprises a DTx-01-65 motif in Table 3. In embodiments, the compound comprises a DTx-01-66 motif in Table 3. In embodiments, the compound comprises a DTx-01-67 motif in Table 3. In embodiments, the compound comprises a DTx-01-68 motif in Table 3. In embodiments, the compound comprises a DTx-01-69 motif in Table 3. In embodiments, the compound comprises a DTx-01-70 motif in Table 3. In embodiments, the compound comprises a DTx-01-71 motif in Table 3. In embodiments, the compound comprises a DTx-01-72 motif in Table 3. In embodiments, the compound comprises a DTx-01-73 motif in Table 3. In embodiments, the compound comprises a DTx-01-74 motif in Table 3. In embodiments, the compound comprises a DTx-01-75 motif in Table 3. In embodiments, the compound comprises a DTx-01-76 motif in Table 3. In embodiments, the compound comprises a DTx-01-77 motif in Table 3. In embodiments, the compound comprises a DTx-01-78 motif in Table 3. In embodiments, the compound comprises a DTx-01-79 motif in Table 3. In embodiments, the compound comprises a DTx-01-80 motif in Table 3. In embodiments, the compound comprises a DTx-01-81 motif in Table 3. In embodiments, the compound comprises a DTx-01-82 motif in Table 3. In embodiments, the compound comprises a DTx-01-83 motif in Table 3. In embodiments, the compound comprises a DTx-01-84 motif in Table 3. In embodiments, the compound comprises a DTx-01-85 motif in Table 3. In embodiments, the compound comprises a DTx-01-86 motif in Table 3. In embodiments, the compound comprises a DTx-01-87 motif in Table 3. In embodiments, the compound comprises a DTx-01-88 motif in Table 3. In embodiments, the compound comprises a DTx-01-89 motif in Table 3. In embodiments, the compound comprises a DTx-01-90 motif in Table 3. In embodiments, the compound comprises a DTx-01-91 motif in Table 3. In embodiments, the compound comprises a DTx-01-92 motif in Table 3. In embodiments, the compound comprises a DTx-01-93 motif in Table 3. In embodiments, the compound comprises a DTx-01-94 motif in Table 3. In embodiments, the compound comprises a DTx-01-95 motif in Table 3. In embodiments, the compound comprises a DTx-01-96 motif in Table 3. In embodiments, the compound comprises a DTx-01-97 motif in Table 3. In embodiments, the compound comprises a DTx-01-98 motif in Table 3. In embodiments, the compound comprises a DTx-01-99 motif in Table 3. In embodiments, the compound comprises a DTx-01-100 motif in Table 3. In embodiments, the compound comprises a DTx-01-101 motif in Table 3. Table 3: Uptake Motif
In embodiments, DTx-01-01 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein , DTx-01-03 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-06 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-08 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-11 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-13 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-30 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-31 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-32 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-33 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-34 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-35 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-36 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-39 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-43 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-44 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-45 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-46 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-50 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-51 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-52 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-53 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-54 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-55 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-03-06 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-03-50 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-03-51 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-03-52 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-03-53 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-03-54 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-03-55 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-04-01 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-05-01 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-06-06 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-06-50 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-06-51 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-06-52 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-06-53 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-06-54 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-06-55 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-08-01 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-09-01 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-10-01 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-11-01 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-60 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-61 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-62 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-63 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-64 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-65 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-66 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-67 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-68 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-69 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-70 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-71 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-72 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-73 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-74 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-75 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-76 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-77 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-78 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-79 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-80 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-81 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-82 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-83 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-84 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-85 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-86 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-87 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-88 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-89 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-90 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-91 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-92 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-93 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-94 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-95 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-96 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-97 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-98 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-99 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-100 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-101 is attached to the double-stranded nucleic acid (A) through -L3- L4-, wherein . In embodiments, DTx-01-01 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein DTx-01-03 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3- . embodiments, DTx-01-06 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-08 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-11 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-13 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-30 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-31 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-32 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-33 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-34 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-35 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-36 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-39 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-43 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-44 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-45 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-46 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-50 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-51 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-52 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-53 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-54 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-55 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-03-06 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-03-50 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-03-51 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-03-52 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-03-53 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-03-54 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-03-55 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-04-01 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-05-01 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-06-06 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-06-50 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-06-51 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein . In embodiments, DTx-06-52 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein . embodiments, DTx-06-53 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-06-54 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein . In embodiments, DTx-06-55 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- i In embodiments, DTx-08-01 is attached to the double-stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-09-01 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-10-01 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-11-01 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-60 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-61 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-62 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-63 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-64 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-65 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-66 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-67 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-68 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-69 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-70 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-71 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-72 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-73 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-74 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-75 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-76 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-77 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-78 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-79 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-80 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-81 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-82 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-83 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-84 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-85 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-86 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-87 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-88 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-89 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-90 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-91 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-92 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . In embodiments, DTx-01-93 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-94 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-95 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-96 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-97 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-98 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-99 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-100 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is . embodiments, DTx-01-101 is attached to the double- stranded nucleic acid (A) through -L3-L4-, wherein -L3-L4- is In embodiments, -L3-L4- i the phosphate group is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L6 is , L5 is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C15 alkyl, and R2 is unsubstituted unbranched C15 alkyl. In embodiments, , the phosphate group of -L3-L4- is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L6 is , L5 is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C13 alkyl, and R2 is unsubstituted unbranched C13 alkyl. In embodiments, , within -L3-L4-, -L3 is attached to a phosphate group at the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L6 is , L5 is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C15 alkyl, and R2 is unsubstituted unbranched C15 alkyl. In embodiments, , within -L3-L4-, -L3 is attached to a phosphate group at the the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L6 is , L5 is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C13 alkyl, and R2 is unsubstituted unbranched C13 alkyl. In embodiments, a compound is selected from DT-000429, DT-000430, DT-000431, DT-000432, DT-000735, DT-000736, DT-000737, DT-000738, DT-000776, DT-000777, DT-000778, DT-000785, DT-000786, DT-000787, DT-000828, DT-000829, DT-000830, DT-000831, and DT-000832. In embodiments, a compound is DT-000429. In embodiments, the compound is DT-000430. In embodiments, a compound is DT-000431. In embodiments, a compound is DT-000432. In embodiments, a compound is DT-000735. In embodiments, a compound is DT-000736. In embodiments, a compound is DT-000737. In embodiments, a compound is DT-000738. In embodiments, a compound is DT-000776. In embodiments, a compound is DT-000777. In embodiments, a compound is DT-000778. In embodiments, a compound is DT-000785. In embodiments, a compound is DT-000786. In embodiments, a compound is DT-000787. In embodiments, a compound is DT-000828. In embodiments, a compound is DT-000829. In embodiments, a compound is DT-000830. In embodiments, a compound is DT-000831. In embodiments, a compound is DT-000832. In embodiments, a compound is DT-001373. In embodiments, a compound is DT-001374. In embodiments, a compound is DT-001375. In embodiments, a compound is DT-001386. The structures of DT-000429, DT-000430, DT-000431, and DT-000432 are shown in Table S. The structures of DT-000735, DT-000736, DT-000737, DT-000738, DT-000776, DT-000777, DT-000778, DT-000785, DT-000786, DT-000787, DT-000828, DT-000829, DT-000830, DT-000831, and DT-000832 are shown in Table AA. The structures of DT-001373, DT-001374, DT-001375, and DT-001376 are shown in Table AA. In embodiments, a compound is DT-000430, where -L3-L4- is , the phosphate group of -L3-L4- is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L6 is , L5 is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C13 alkyl, R2 is unsubstituted unbranched C13 alkyl, the nucleotide sequence of the sense strand is 5’- GF SGM SAFAMUFAMUFGMUFCMAFAMUFGMAFCMUF SUM SUF-3’ (SEQ ID NO: 265), and the nucleotide sequence of the antisense strand is 5’- AMSAFSAMGFUMCFAMUFUMGFAMCFAMUFAMUFUMCFCMSTST-3’ (SEQ ID NO: 37), where a nucleotide followed by the subscript “F” is a 2’-fluoro nucleotide; a nucleotide followed by the subscript “M” is a 2’-O-methyl nucleotide; a nucleotide without a subscript is a beta-D-deoxyribonucleotide; a superscript “S” is a phosphorothioate internucleotide linkage; and all other internucleotide linkages are phosphodiester internucleotide linkages. In embodiments, a compound is DT-000432, where -L3-L4- is , the phosphate group of -L3-L4- is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L6 is , L5 is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C13 alkyl, R2 is unsubstituted unbranched C13 alkyl, the nucleotide sequence of the sense strand is 5’- UF SGM SAFCMUFUMUFGMAFCMUFUMGFAMUFGMAF SAM SGF-3’ (SEQ ID NO: 267), and the nucleotide sequence of the antisense strand is 5’- CMSUFSUMCFAMUFCMAFAMGFUMCFAMAFAMGFUMCFAMSTST-3’ (SEQ ID NO: 57), where a nucleotide followed by the subscript “F” is a 2’-fluoro nucleotide; a nucleotide followed by the subscript “M” is a 2’-O-methyl nucleotide; a nucleotide without a subscript is a beta-D-deoxyribonucleotide; a superscript “S” is a phosphorothioate internucleotide linkage; and all other internucleotide linkages are phosphodiester internucleotide linkages. In embodiments, a compound is DT-000776, where -L3-L4- is , the phosphate group of -L3-L4- is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L6 is , L5 is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C13 alkyl, R2 is unsubstituted unbranched C13 alkyl, the nucleotide sequence of the sense strand is 5’- AF SUM SGFGMAFAMUFAMUFGMUFCMAFAMUFGMAFCMUF SUM SUF-3’ (SEQ ID NO: 222), and the nucleotide sequence of the antisense strand is 5’- AMSAFSAMGFUMCFAMUFUMGFAMCFAMUFAMUFUMCFCMAFUMSGMSGM-3’ (SEQ ID NO: 213), where a nucleotide followed by the subscript “F” is a 2’-fluoro nucleotide; a nucleotide followed by the subscript “M” is a 2’-O-methyl nucleotide; a superscript “S” is a phosphorothioate internucleotide linkage; and all other internucleotide linkages are phosphodiester internucleotide linkages. In embodiments, a compound is DT-001373, where -L3-L4- is , the phosphate group of -L3-L4- is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L6 is L5 is -NHC(O)-, 3 s hydrogen, R1 R i is unsubstituted unbranched C13 alkyl, R2 is unsubstituted unbranched C13 alkyl, the nucleotide sequence of the sense strand is 5’- CFSUMSUFUMGFAMCFUMUFGMAFUMGFAMAFGMUFUMUFSGMSAF-3’ (SEQ ID NO: 242), and the nucleotide sequence of the antisense strand is 5’- UM SCF SAMAFAMCFUMUFCMAFUMCFAMAFGMUFCMAFAMAFGM SUM SCM-3’ (SEQ ID NO: 239), where a nucleotide followed by the subscript “F” is a 2’-fluoro nucleotide; a nucleotide followed by the subscript “M” is a 2’-O-methyl nucleotide; a superscript “S” is a phosphorothioate internucleotide linkage; and all other internucleotide linkages are phosphodiester internucleotide linkages. In embodiments a compound is DT-001374, where -L3-L4- is the phosphate group of -L3-L4- is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L6 is , is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C13 alkyl, R2 is unsubstituted unbranched C13 alkyl, the nucleotide sequence of the sense strand is 5’- UFSGMSAFCMUFUMGFAMUFGMAFAMGFUMUFUMGFAMGFSGMSUF-3’ (SEQ ID NO: 243), and the nucleotide sequence of the antisense strand is 5’- AM SCF SCMUFCMAFAMAFCMUFUMCFAMUFCMAFAMGFUMCFAM SAM SAM-3’ (SEQ ID NO: 240), where a nucleotide followed by the subscript “F” is a 2’-fluoro nucleotide; a nucleotide followed by the subscript “M” is a 2’-O-methyl nucleotide; a superscript “S” is a phosphorothioate internucleotide linkage; and all other internucleotide linkages are phosphodiester internucleotide linkages. In embodiments, a compound is DT-001375, where -L3-L4- is , the phosphate group of -L3-L4- is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L6 is , L5 is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C13 alkyl, R2 is unsubstituted unbranched C13 alkyl, the nucleotide sequence of the sense strand is 5’- CF SUM SUFGMAFUMGFAMAFGMUFUMUFGMAFGMGFUMAF SAM SAF-3’ (SEQ ID NO: 244), and the nucleotide sequence of the antisense strand is 5’- UMSUFSUMAFCMCFUMCFAMAFAMCFUMUFCMAFUMCFAMAFGMSUMSCM-3’ (SEQ ID NO: 241), where a nucleotide followed by the subscript “F” is a 2’-fluoro nucleotide; a nucleotide followed by the subscript “M” is a 2’-O-methyl nucleotide; a superscript “S” is a phosphorothioate internucleotide linkage; and all other internucleotide linkages are phosphodiester internucleotide linkages. In embodiments, a compound is DT-001386, where -L3-L4- is , the phosphate group of -L3-L4- is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, L6 is , L5 is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C13 alkyl, R2 is unsubstituted unbranched C13 alkyl, the nucleotide sequence of the sense strand is 5’- AM SUM SGFGMAFAMUFAMUFGMUFCMAFAMUFGMAFCMUF SUM SUF-3’ (SEQ ID NO: 245), and the nucleotide sequence of the antisense strand is 5’- AMSAFSAMGFUMCFAMUFUMGFAMCFAMUFAMUFUMCFCMAFUMSGMSGM-3’ (SEQ ID NO: 213), where a nucleotide followed by the subscript “F” is a 2’-fluoro nucleotide; a nucleotide followed by the subscript “M” is a 2’-O-methyl nucleotide; a superscript “S” is a phosphorothioate internucleotide linkage; and all other internucleotide linkages are phosphodiester internucleotide linkages. In embodiments, a ligand is a saturated or unsaturated C8-C20 alkyl. In embodiments, a ligand contains a saturated or unsaturated C6-C18 alkyl. Pharmaceutical Salts and Compositions The compounds provided herein may be present as a pharmaceutical salt. In embodiments, the pharmaceutical salt is a sodium salt. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297, Johnston et al., published September 11, 1987 (incorporated by reference herein in its entirety). In embodiments, a non-bridging heteroatom (e.g., an S− or O−) of a linkage of a compound provided herein may be protonated or associated with a counterion such as Na+, K+, etc. An acceptable salt (e.g. a pharmaceutically acceptable salt) of a compound may comprise fewer cationic counterions (such as Na+, K+, etc.) than there are non-bridging heteroatoms per molecule (i.e., some non-bridging heteroatoms are protonated and some are associated with counterions). In embodiments, a phosphate linkage attaching an -L3-L4- to a carbon of a nucleotide includes a non-bridging heteroatom. In embodiments, a phosphodiester linkage of a nucleic acid includes a non-bridging heteroatom. In embodiments, a phosphorothioate linkage of a nucleic acid includes a non-bridging heteroatom. The compounds provided herein may be present as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable diluent. In embodiments, the compound is present in a pharmaceutically acceptable diluent. In embodiments, the pharmaceutically acceptable diluent is a sterile aqueous solution. In embodiments, the sterile aqueous solution is a sterile saline solution. A pharmaceutical composition may be prepared so that it is compatible with the intended mode of administration of the compound. Routes of administration of compounds include intravenous, intradermal, subcutaneous, transdermal, intramuscular, topical, and ocular administration. Pharmaceutical compositions may be prepared for ocular administration to the eye in the form of an injection. Pharmaceutical compositions suitable for injection include sterile aqueous solutions, including sterile saline solutions. Pharmaceutical compositions suitable for injection may also be a lyophilized compound that is subsequently reconstitute with a pharmaceutically acceptable diluent in preparation for injection. Alternatively, pharmaceutical compositions may be prepared for ocular administration to the eye in the form of an ophthalmic suspension (i.e. eye drops). Additional pharmaceutical preparations suitable for ocular administration include emulsions, ointments, aqueous gels, nanomicelles, nanoparticles, liposomes, dendrimers, implants, contact lenses, nanosuspensions, microneedles, and in situ thermosensitive gels. Methods of Use The compounds provided herein inhibit the expression of the neural retina leucine zipper (NRL) mRNA. Provided herein is a method for inhibiting the expression of neural retina leucine zipper (NRL) mRNA in a cell, comprising contacting a cell with a nucleic compound provided herein, thereby inhibiting the expression of neural retina leucine zipper (NRL) in the cell. In embodiments, the cell is a photoreceptor cell. In embodiments, the cell is in vivo. In embodiments, the cell is in vitro. Provided herein is a method for inhibiting the expression of neural retina leucine zipper (NRL) in a subject, comprising administering to the subject an effective amount of a compound provided herein, thereby inhibiting the expression of neural retina leucine zipper (NRL) in the subject. Provided herein is a method for treating retinitis pigmentosa in a subject in need thereof, comprising administering to the subject an effective amount compound provided herein. Provided herein is a method for delaying the onset of retinitis pigmentosa in a subject in need thereof, comprising administering to the subject a compound provided herein. Retinitis pigmentosa may be diagnosed by a medical professional using one or more available examination procedures which are routine tests of vision and retinal function. Nyctalopia, or impaired vision at night or in low lighting, is an indicator of retinitis pigmentosa. Additionally, subjects with retinitis pigmentosa may exhibit visual field constriction, which is an absolute or relative decrease in retinal sensitivity and may be determined by mapping the visual field of each eye of the subject to assess the subject’s scope of vision (central and peripheral vision). Further, subjects with retinitis pigmentosa may exhibit decreased visual acuity, which is often determined by the ability of the subject to identify letters or numbers on a standardized eye chart from a specific viewing distance. Morphological abnormalities in the retina may be found in subject with retinitis pigmentosa and may be detected by optical coherence tomography (OCT), which is a method of examining the retinal structure in situ. Subjects with retinitis pigmentosa may exhibit a reduced electrical responses of various cell types in the retina, including photoreceptor cells, to a light stimulus. The electrical activity generated in retinal cells in response to a light stimulus may be measured by an electroretinogram (ERG). Additionally, an examination of the retina in subjects may identify abnormal retinal pigmentation, or dark pigment deposits in the retina of the subject. In embodiments, prior to administration of the compound to the subject, the subject has been diagnosed as having retinitis pigmentosa. In embodiments, a subject is diagnosed as having retinitis pigmentosa based on one or more indicators of the disease: a family history of retinitis pigmentosa; decreased visual acuity; abnormal retinal morphology; the presence of nyctalopia; visual field constriction; a reduced response to light stimulus; and retinal pigmentation abnormalities. In embodiments, the administration of the compound to the subject improves one or more indicators of retinitis pigmentosa in the subject. In embodiments, administration of the compound to the subject slows the progression of one or more indicators of retinitis pigmentosa in the subject. In embodiments, an indicator is visual acuity. In embodiments, an indicator is retinal morphology. In embodiments, an indicator is nyctalopia. In embodiments, an indicator is visual field constriction. In embodiments, an indicator is response to a light stimulus. In embodiments, a response to a light stimulus is measured by a electroretinogram. In embodiments, an indicator is retinal pigmentation. Compounds provided herein may be administered via ocular administration. In embodiments, ocular administration is intraocular administration. Intraocular administration is achieved by injection into a specific area of the eye. In embodiments, intraocular administration is subconjunctival administration. In embodiments, intraocular administration is intravitreal administration. In embodiments, intraocular administration is retrobulbar administration. In embodiments, intraocular administration is intracameral administration. In embodiments, ocular administration is topical administration. In embodiments, topical administration comprises administration of an ophthalmic suspension. In embodiments, topical administration comprises administration of an ointment. In embodiments, at least one additional therapy is administered to the subject. In embodiments, the at least one additional therapy is vitamin A. In embodiments, compounds provided herein are for use in therapy. In embodiments, pharmaceutical compositions provided herein are for use in therapy. In embodiments, the therapy is the treatment of retinitis pigmentosa. Formulations Various formulations are available to facilitate compound use both in vitro and as therapeutic agents. Accordingly, in embodiments, a compound provided herein is present in a formulation. Compounds may be formulated with cationic lipids to facilitate transfection into cells. Suitable cationic lipid reagents for transfection include Lipofectamine reagents, such as Lipofectamine RNAiMAX. For use in vivo as therapeutic agents, nucleic acids compounds may be encapsulated into lipid nanoparticles. Lipid nanoparticles generally comprise a cationic lipid, a non-cationic lipid, and a lipid that prevents aggregation of the nanoparticle. Suitable cationic lipids include DLin-MC3-DMA ((6Z,9Z,28Z,31Z)-Heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate), DLin-KC2-DMA (2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane) and the lipidoid C12-200. Suitable non-cationic lipids include, for example, DOPC (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine) and DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine). Examples of lipids that prevent aggregation include, for example, polyethylene glycol (PEG)-lipids, such as PEG-C-DMA (3-N-[(ω-methoxypoly(ethylene glycol)2000)carbamoyl]-1,2-dimyristyloxy-propylamine), PEG2000-C-DMG (α-(3-{[1,2-di(myristyloxy)proponoxy]carbonylamino}propyl)-ω-methoxy, polyoxyethylene), and mPEG-DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]). Embodiments Embodiment P1. A compound comprising an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein each of the antisense strand and sense strands is 15 to 25 nucleotides in length, the nucleotide sequence of the antisense strand is at least 90% complementary to the nucleotide sequence of the NRL mRNA (SEQ ID NO: 1), and the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand. Embodiment P2. The compound of Embodiment P1, wherein each of the antisense strand and sense strands is 15 to 25 nucleotides in length, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 contiguous nucleotides of any one of nucleotides 501 to 563 of SEQ ID NO: 1, nucleotides 602 to 626 of SEQ ID NO: 1, nucleotides 623 to 654 of SEQ ID NO: 1, nucleotides 684 to 710 of SEQ ID NO: 1, nucleotides 741 to 765 of SEQ ID NO: 1, nucleotides 759 to 777 of SEQ ID NO: 1, nucleotides 882 to 909 of SEQ ID NO: 1, or nucleotides 1111 to 1133 of SEQ ID NO: 1, and the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand. Embodiment P3. The compound of Embodiment P1 or P2, wherein the antisense strand is 17 to 23 nucleotides in length. Embodiment P4. The compound of any one of Embodiments P1 to P3, wherein the antisense strand is 19 to 21 nucleotides in length. Embodiment P5. The compound of any one of Embodiments P1 to P3, wherein the antisense strand is 21 to 23 nucleotides in length. Embodiment P6. The compound of any one of Embodiments P1 to P5, wherein the antisense strand is 19 nucleotides in length. Embodiment P7. The compound of any one of Embodiments P1 to P5, wherein the antisense strand is 20 nucleotides in length. Embodiment P8. The compound of any one of Embodiments P1 to P5, wherein the antisense strand is 21 nucleotides in length. Embodiment P9. The compound of any one of Embodiments P1 to P5, wherein the antisense strand is 22 nucleotides in length. Embodiment P10. The compound of any one of Embodiments P1 to P5, wherein the antisense strand is 23 nucleotides in length. Embodiment P11. The compound of any one of Embodiments P1 to P10, wherein the sense strand is 17 to 23 nucleotides in length. Embodiment P12. The compound of any one of Embodiments P1 to P10, wherein the sense strand is 19 to 21 nucleotides in length. Embodiment P13. The compound of any one of Embodiments P1 to P10, wherein the sense strand is 21 to 23 nucleotides in length. Embodiment P14. The compound of any one of Embodiments P1 to P13, wherein the sense strand is 19 nucleotides in length. Embodiment P15. The compound of any one of Embodiments P1 to P13, wherein the sense strand is 20 nucleotides in length. Embodiment P16. The compound of any one of Embodiments P1 to P13, wherein the sense strand is 21 nucleotides in length. Embodiment P17. The compound of any one of Embodiments P1 to P13 wherein the sense strand is 22 nucleotides in length. Embodiment P18. The compound of any one of Embodiments P1 to P13, wherein the sense strand is 23 nucleotides in length. Embodiment P19. The compound of any one of Embodiments P1 to P18, wherein the double-stranded region is 15 to 25 nucleotide pairs in length. Embodiment P20. The compound of any one of Embodiments P1 to P18, wherein the double-stranded region is 17 to 23 nucleotide pairs in length. Embodiment P21. The compound of any one of Embodiments P1 to P18, wherein the double-stranded region is 19 to 21 nucleotide pairs in length. Embodiment P22. The compound of any one of Embodiments P1 to P18, wherein the double-stranded region is 19 nucleotide pairs in length. Embodiment P23. The compound of any one of Embodiments P1 to P18, wherein the double-stranded region is 20 nucleotide pairs in length. Embodiment P24. The compound of any one of Embodiments P1 to P18, wherein the double-stranded region is 21 nucleotide pairs in length. Embodiment P25. The compound of any one of Embodiments P1 to P24, wherein the nucleotide sequence of the sense strand has no more than one mismatch to the nucleotide sequence of the antisense strand. Embodiment P26. The compound of any one of Embodiments P1 to P24, wherein the nucleotide sequence of the sense strand has no mismatches to the nucleotide sequence of the antisense strand. Embodiment P27. The compound of any one of Embodiments P3 to P26, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. Embodiment P28. The compound of Embodiment P27, wherein the nucleotide sequence of the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75. Embodiment P29. The compound of Embodiment P28, wherein the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75. Embodiment P30. The compound of Embodiment P28, wherein the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75. Embodiment P31. The compound of Embodiment P28, wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 63, 65, 25, 33, 35, 37, 39, 29, 41, 43, 45, 47, 49, 51, 53, 55, 27, 57, 59, 61, 67, 69, 71, 73, and 75, and wherein the nucleotide sequence of the antisense strand is 100% complementary to 23 contiguous nucleotides of SEQ ID NO: 1. Embodiment P32. The compound of any one of Embodiments P27 to P31, wherein the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74. Embodiment P33. The compound of any one of Embodiments P27 to P31, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74. Embodiment P34. The compound of any one of Embodiments P27 to P31, wherein the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74. Embodiment P35. The compound of any one of Embodiments P27 to P31, wherein the sense strand is 21 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 62, 64, 24, 32, 34, 36, 38, 28, 40, 42, 44, 46, 48, 50, 52, 54, 26, 56, 58, 60, 66, 68, 70, 72, and 74, and wherein the nucleotide sequence of the sense strand is identical to 21 contiguous nucleotides of SEQ ID NO: 1. Embodiment P36. The compound of any one of Embodiments P3 to P26, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. Embodiment P37. The compound of Embodiment P36, wherein the nucleotide sequence of the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 93, 95, and 97. Embodiment P38. The compound of Embodiment P37, wherein the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 93, 95, and 97. Embodiment P39. The compound of Embodiment P37, wherein the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 93, 95, and 97. Embodiment P40. The compound of Embodiment P37, wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96, and wherein the nucleotide sequence of the antisense strand is 100% complementary 23 contiguous nucleotides of SEQ ID NO: 1. Embodiment P41. The compound of any one of Embodiments P36 to P40, wherein the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96. Embodiment P42. The compound of any one of Embodiments P36 to P40, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96. Embodiment P43. The compound of any one of Embodiments P36 to P40, wherein the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96. Embodiment P44. The compound of any one of Embodiments P36 to P40, wherein the sense strand is 21 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 92, 94, and 96, and wherein the nucleotide sequence of the sense strand is identical to 21 contiguous nucleotides of SEQ ID NO: 1. Embodiment P45. The compound of any one of Embodiments P3 to P26, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. Embodiment P46. The compound of Embodiment P45, wherein the nucleotide sequence of the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109. Embodiment P47. The compound of Embodiment P46, wherein the nucleotide sequence of antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109. Embodiment P48. The compound of Embodiment P46, wherein the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109. Embodiment P49. The compound of Embodiment P46, wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 9, 11, 3, 5, 105, 107, and 109, and wherein the nucleotide sequence of the antisense strand is 100% complementary 23 contiguous nucleotides of SEQ ID NO: 1. Embodiment P50. The compound of any one of Embodiments P45 to P49, wherein the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 8, 10, 2, 4, 104, 106, and 108. Embodiment P51. The compound of any one of Embodiments P45 to P49, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 8, 10, 2, 4, 104, 106, and 108. Embodiment P52. The compound of any one of Embodiments P45 to P49, wherein the sense strand is 19 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 8, 10, 2, 4, 104, 106, and 108. Embodiment P53. The compound of any one of Embodiments P45 to P49, wherein the sense strand is 21 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 8, 10, 2, 4, 104, 106, and 108, and wherein the nucleotide sequence of the sense strand is identical to a 21 contiguous nucleotides of SEQ ID NO: 1. Embodiment P54. The compound of any one of Embodiments P3 to P26, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. Embodiment P55. The compound of Embodiment P54, wherein the nucleotide sequence of the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119. Embodiment P56. The compound of Embodiment P55, wherein the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119. Embodiment P57. The compound of Embodiment P55, wherein the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119. Embodiment P58. The compound of Embodiment P55, wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 115, 117, and 119, and wherein the nucleotide sequence of the antisense strand is 100% complementary 23 contiguous nucleotides of SEQ ID NO: 1. Embodiment P59. The compound of any one of Embodiments P54 to P58, wherein the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 114, 116, and 118. Embodiment P60. The compound of any one of Embodiments P54 to P58, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 114, 116, and 118. Embodiment P61. The compound of any one of Embodiments P54 to P58, wherein the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 114, 116, and 118. Embodiment P62. The compound of any one of Embodiments P54 to P58, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 114, 116, and 118, and wherein the nucleotide sequence of the sense strand is identical to 21 contiguous nucleotides of SEQ ID NO: 1. Embodiment P63. The compound of Embodiment P62, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. Embodiment P64. The compound of Embodiment P63, wherein the nucleotide sequence of the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20 or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133. Embodiment P65. The compound of Embodiment P64, wherein the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133. Embodiment P66. The compound of Embodiment P64, wherein the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133. Embodiment P67. The compound of Embodiment P64, wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 129, 131, and 133, and wherein the nucleotide sequence of the antisense strand is 100% complementary to 23 contiguous nucleotides of SEQ ID NO: 1. Embodiment P68. The compound of any one of Embodiments P63 to P67, wherein the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 128, 130, and 132. Embodiment P69. The compound of any one of Embodiments P63 to P67, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 128, 130, and 132. Embodiment P70. The compound of any one of Embodiments P63 to P67, wherein the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 128, 130, and 132. Embodiment P71. The compound of any one of Embodiments P63 to P67, wherein the sense strand is 21 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 128, 130, and 132, and wherein the nucleotide sequence of the sense strand is identical to 21 contiguous nucleotides of SEQ ID NO: 1. Embodiment P72. The compound of any one of Embodiments P3 to P26, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, or 19 contiguous nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. Embodiment P73. The compound of Embodiment P72, wherein the nucleotide sequence of the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or 21 contiguous nucleotides of SEQ ID NO: 141. Embodiment P74. The compound of Embodiment P73, wherein the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of SEQ ID NO: 141. Embodiment P75. The compound of Embodiment P73, wherein antisense strand is 21 nucleotides in length and comprises a nucleotide sequence that is identical to the nucleotide sequence of SEQ ID NO: 141. Embodiment P76. The compound of Embodiment P73, wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of the nucleotide sequence of SEQ ID NO: 141, and wherein the nucleotide sequence of the antisense strand is 100% complementary to 23 contiguous nucleotides of SEQ ID NO: 1. Embodiment P77. The compound of any one of Embodiments P72 to P76, wherein the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of SEQ ID NO: 140. Embodiment P78. The compound of any one of Embodiments P72 to P76, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to the nucleotide sequence of SEQ ID NO: 140. Embodiment P79. The compound of any one of Embodiments P72 to P76, wherein the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to the nucleotide sequence of SEQ ID NO: 140. Embodiment P80. The compound of any one of Embodiments P72 to P76, wherein the sense strand is 21 nucleotides in length and nucleotides 1 to 19 of the nucleotide sequence of SEQ ID NO: 140, and wherein the nucleotide sequence of the sense strand is identical to 21 contiguous nucleotides of SEQ ID NO: 1. Embodiment P81. The compound of any one of Embodiments P3 to P26, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 882 to 909 of SEQ ID NO: 1. Embodiment P82. The compound of Embodiment P81, wherein the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20 or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19. Embodiment P83. The compound of Embodiment P82, wherein the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19. Embodiment P84. The compound of Embodiment P82, wherein the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19. Embodiment P85. The compound of Embodiment P82, wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 171, 173, 23, 13, 15, 17, and 19, and wherein the nucleotide sequence of the antisense strand is 100% complementary to 23 contiguous nucleotides of SEQ ID NO: 1. Embodiment P86. The compound of any one of Embodiments P81 to P85, wherein the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID: 170, 172, 22, 12, 14, 16, and 18. Embodiment P87. The compound of any one of Embodiments P81 to P85, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID: 170, 172, 22, 12, 14, 16, and 18. Embodiment P88. The compound of any one of Embodiments P81 to P85, wherein the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID: 170, 172, 22, 12, 14, 16, and 18. Embodiment P89. The compound of any one of Embodiments P81 to P85, wherein the sense strand is 21 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID: 170, 172, 22, 12, 14, 16, and 18, and wherein the nucleotide sequence of the sense strand is identical to 21 contiguous nucleotides of SEQ ID NO: 1. Embodiment P90. The compound of any one of Embodiments P3 to P26, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or 23 contiguous nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. Embodiment P91. The compound of Embodiment P90, wherein the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20 or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 193 and 195. Embodiment P92. The compound of Embodiment P91, wherein the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 193 and 195. Embodiment P93. The compound of Embodiment P91, wherein the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 193 and 195. Embodiment P94. The compound of Embodiment P91, wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 193 and 195, and wherein the nucleotide sequence of the antisense strand is 100% complementary to 23 contiguous nucleotides of SEQ ID NO: 1. Embodiment P95. The compound of any one of Embodiments P90 to P94, wherein the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 192 and 194. Embodiment P96. The compound of any one of Embodiments P90 to P94, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 192 and 194. Embodiment P97. The compound of any one of Embodiments P90 to P94, wherein the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 192 and 194. Embodiment P98. The compound of any one of Embodiments P90 to P94, wherein the sense strand is 21 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 192 and 194, and wherein the nucleotide sequence of the sense strand is identical to a 21-nucleotide contiguous nucleotides of SEQ ID NO: 1. Embodiment P99. The compound of any one of Embodiments P1 to P97, wherein the nucleotide sequence of the antisense strand is at least 95% complementary to SEQ ID NO: 1. Embodiment P100. The compound of any one of Embodiments P1 to P99, wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1. Embodiment P101. The compound of any one of Embodiments P1 to P100, wherein the antisense strand and the sense strand are not covalently linked. Embodiment P102. The compound of any one of Embodiments P1 to P99, wherein the hybridization of the antisense strand to the sense strand forms at least one blunt end. Embodiment P103. The compound of Embodiment P102, wherein the hybridization of the antisense strand to the sense strand forms a blunt end at each terminus of the compound. Embodiment P104. The compound of any one of Embodiments P1 to P102, wherein at least one strand comprises a 3’ nucleotide overhang of one to five nucleotides. Embodiment P105. The compound of Embodiment P104, wherein the sense strand comprises the 3’ nucleotide overhang. Embodiment P106. The compound of Embodiment P104, wherein the antisense strand comprises the 3’ nucleotide overhang. Embodiment P107. The compound of Embodiment P104, wherein each of the sense strand and the antisense strand comprises a 3’ nucleotide overhang of one to five nucleotides. Embodiment P108. The compound of Embodiment P106 or Embodiment P107, wherein each nucleotide of the 3’ nucleotide overhang of the antisense strand is complementary to SEQ ID NO: 1. Embodiment P109. The compound of Embodiment P106 or Embodiment P107, wherein each nucleotide of the 3’ nucleotide overhang of the antisense strand is not complementary to SEQ ID NO: 1 Embodiment P110. The compound of any one of Embodiments P104 to P109, wherein each nucleotide of the 3’ nucleotide overhang is a deoxythymidine. Embodiment P111. The compound of any one of Embodiments P104 to P110, wherein the 3’ nucleotide overhang is two nucleotides in length. Embodiment P112. The compound of any one of Embodiments P1 to P111, wherein at least one nucleotide of the antisense strand is a modified nucleotide. Embodiment P113. The compound of any one of Embodiments P1 to P112, wherein at least one nucleotide of the sense strand is a modified nucleotide. Embodiment P114. The compound of any one of Embodiments P1 to P113, wherein each nucleotide of the antisense strand forming the double-stranded region is a modified nucleotide. Embodiment P115. The compound of any one of Embodiments P1 to P114, wherein each nucleotide of the sense strand forming the double-stranded region is a modified nucleotide. Embodiment P116. The compound of any one of Embodiments P112 to P115, wherein the modified nucleotide comprises one or more of a modified sugar moiety, a modified internucleotide linkage, and a 5’-terminal modified phosphate group. Embodiment P117. The compound of Embodiment P116, wherein the modified nucleotide comprising a modified sugar moiety is selected from a 2’-fluoro nucleotide, a 2’- O-methyl nucleotide, a 2’-O-methoxyethyl nucleotide, and a bicyclic sugar nucleotide. Embodiment P118. The compound of Embodiment P116, wherein the modified internucleotide linkage is a phosphorothioate internucleotide linkage. Embodiment P119. The compound of Embodiment P118, wherein the first two internucleotide linkages at the 5’ terminus of the sense strand and the last two internucleotide linkages at the 3’ terminus of the sense strand are phosphorothioate internucleotide linkages. Embodiment P120. The compound of Embodiment P119, wherein the first two internucleotide linkages at the 5’ terminus of the antisense strand and the last two internucleotide linkages at the 3’ terminus of the antisense strand are phosphorothioate internucleotide linkages. Embodiment P121. The compound of Embodiment P117, wherein the covalent linkage of the bicyclic sugar is selected from a 4’-CH(CH3)-O-2’ linkage, a 4'-(CH2)2-O-2' linkage, a 4'-CH(CH2-OMe)-O-2' linkage, 4’-CH2-N(CH3)-O-2’ linkage, and 4’-CH2-N(H)- O-2’ linkage. Embodiment P122. The compound of Embodiment P117, wherein the 5’-terminal modified phosphate group is a 5’-(E)-vinylphosphonate. Embodiment P123. The compound of any one of Embodiments P1 to P122, wherein the antisense strand is 21 nucleotides in length, and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O- methylnucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-flouronucleotides, and nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P124. The compound of any one of Embodiments P1 to P122, wherein the antisense strand is 19 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O- methylnucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-flouronucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P125. The compound of Embodiment P123 or Embodiment P124, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’- fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides, and nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P126. The compound of Embodiment P123 or Embodiment P124, wherein the sense strand is 19 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoro nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P127. The compound of any one of Embodiments P1 to P122, wherein the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methylnucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’- flouronucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P128. The compound of Embodiment P127, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P129. The compound of Embodiment P127, wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta- D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage Embodiment P130. The compound of any one of Embodiments P1 to P122, wherein the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methylnucleotides and nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’- flouronucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P131. The compound of Embodiment P130, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P132. The compound of Embodiment P130, wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta-D- deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P133. The compound of any one of Embodiments P1 to P122, wherein the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methylnucleotides and nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’- flouronucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P134. The compound of Embodiment P133, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-O-methyl nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P135. The compound of Embodiment P133, wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta-D- deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P136. The compound of any one of Embodiments P1 to P135, wherein the compound comprises a ligand covalently linked to the double-stranded nucleic acid. Embodiment P137. The compound of Embodiment P136, wherein the compound has the structure: wherein A is the double-stranded nucleic acid; wherein t is an integer from 1 to 5; L3 and L4 are independently a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, -C(O)N(R24)-, -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O-P(S)(NR23R24)-N-, -O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; L5 is -L5A-L5B-L5C-L5D-L5E-; L6 is -L6A-L6B-L6C-L6D-L6E-; R1 and R2 are independently unsubstituted C1-C25 alkyl, wherein at least one of R1 and R2 is unsubstituted C9-C19 alkyl; R3 is hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, –N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L5A, L5B, L5C, L5D, L5E, L6A, L6B, L6C, L6D, and L6E are independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, –C(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; and each R23, R24 and R25 is independently hydrogen or unsubstituted C1-C10 alkyl. Embodiment P138. The compound of Embodiment P137, wherein t is 1. Embodiment P139. The compound of Embodiment P137, wherein t is 2. Embodiment P140. The compound of Embodiment P137, wherein t is 3. Embodiment P141. The compound of any one of Embodiments P137 to P140, wherein A is the sense strand. Embodiment P142. The compound of any one of Embodiments P137 to P141, wherein A is the antisense strand. Embodiment P143. The compound of one of Embodiments P137 to P142, wherein each of R23, R24 and R25 is independently hydrogen or unsubstituted C1-C3 alkyl. Embodiment P144. The compound of one of Embodiments P137 to P143, wherein one L3 is attached to a 3’ carbon of a nucleotide. Embodiment P145. The compound of Embodiment P144, wherein the 3’ carbon is the 3’ carbon of a 3’ terminal nucleotide. Embodiment P146. The compound of one of Embodiments P137 to P141, wherein one L3 is attached to a 5’ carbon of a nucleotide. Embodiment P147. The compound of Embodiment P146, wherein the 5’ carbon is the 5’ carbon of a 5’ terminal nucleotide. Embodiment P148. The compound of one of Embodiments P137 to P141, wherein one L3 is attached to a 2’ carbon of a nucleotide. Embodiment P149. The compound of one of Embodiments P137 to P148, wherein L3 and L4 are independently a bond, -NH-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -OPO2-O-, -O- P(O)(S)-O-, -O-P(O)(CH3)-O-, -O-P(S)(CH3)-O-, -O-P(O)(N(CH3)2)-N-, -O-P(O)(N(CH3)2)- O-, -O-P(S)(N(CH3)2)-N-, -O-P(S)(N(CH3)2)-O-, - P(O)(N(CH3)2)-N-, -P(O)(N(CH3)2)-O-, - P(S)(N(CH3)2)-N-, -P(S)(N(CH3)2)-O-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. Embodiment P150. The compound of one of Embodiments P137 to P149, wherein L3 is independently . Embodiment P151. The compound of one of Embodiments P137 to P149, wherein L3 is independently -OPO2-O- or –OP(O)(S)-O-. Embodiment P152. The compound of one of Embodiments P137 to P149, wherein L3 is independently –O-. Embodiment P153. The compound of any one of Embodiments P137 to P149, wherein L3 is independently -C(O)-. Embodiment P154. The compound of any one of Embodiments P137 to P149, wherein L3 is independently -O-P(O)(N(CH3)2)-N-. Embodiment P155. The compound of one of Embodiments P137 to P152, wherein L4 is independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. Embodiment P156. The compound of one of Embodiments P137 to P155, wherein L4 is independently –L7-NH-C(O)- or –L7-C(O)-NH-, wherein L7 is substituted or unsubstituted alkylene. Embodiment P157. The compound of one of Embodiments P137 to P156, wherein L4 is independently . Embodiment P158. The compound of one of Embodiments P137 to P156, wherein L4 is independently . Embodiment P159. The compound of one of Embodiments P137 to P158, wherein –L3-L4- is independently –O-L7-NH-C(O)- or –O-L7-C(O)-NH-, wherein L7 is independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene. Embodiment P160. The compound of Embodiment P159, wherein –L3-L4- is independently –O-L7-NH-C(O)-, wherein L7 is independently substituted or unsubstituted C5- C8 alkylene. Embodiment P161. The compound of Embodiment P160, wherein –L3-L4- is . Embodiment P162. The compound of one of Embodiments P137 to P149, wherein –L3-L4- is independently -OPO2-O-L7-NH-C(O)-, -OP(O)(S)-O-L7-NH-C(O)-, -OPO2-O-L7- C(O)-NH-or –OP(O)(S)-O-L7-C(O)-NH-, wherein L7 is independently substituted or unsubstituted alkylene. Embodiment P163. The compound of Embodiment P162, wherein –L3-L4- is independently -OPO2-O-L7-NH-C(O)- or –OP(O)(S)-O-L7-NH-C(O)-, wherein L7 is independently substituted or unsubstituted C5-C8 alkylene. Embodiment P164. The compound of Embodiment P163, wherein –L3-L4- is Embodiment P165. The compound of Embodiment P164, wherein an –L3-L4- is carbon of a 3’ terminal nucleotide. Embodiment P166. The compound of Embodiment P164, wherein an –L3-L4- is attached to the 5’ carbon of a 5’ terminal nucleotide. Embodiment P167. The compound of Embodiment P164, wherein an –L3-L4- is independently and is attached to a 2’ carbon. Embodiment P168. The compound of one of Embodiments P127 to P167, wherein R3 is independently hydrogen. Embodiment P169. The compound of one of Embodiments P127 to P168, wherein L6 is independently -NHC(O)-, –C(O)NH-,substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. Embodiment P170. The compound of Embodiment P169, wherein L6 is independently -NHC(O)-. Embodiment P171. The compound of Embodiment P169, wherein L6A is independently a bond or unsubstituted alkylene; L6B is independently a bond, -NHC(O)-, or unsubstituted arylene; L6C is independently a bond, unsubstituted alkylene, or unsubstituted arylene; L6D is independently a bond or unsubstituted alkylene; and L6E is independently a bond or -NHC(O)-. Embodiment P172. The compound of Embodiment P169, wherein L6A is independently a bond or unsubstituted C1-C8 alkylene; L6B is independently a bond, -NHC(O)-, or unsubstituted phenylene; L6C is independently a bond, unsubstituted C2-C8 alkynylene, or unsubstituted phenylene; L6D is independently a bond or unsubstituted C1-C8 alkylene; and L6E is independently a bond or -NHC(O)-. Embodiment P173. The compound of one of Embodiments P127 to P168, wherein Embodiment P174. The compound of one of Embodiments P127 to P173, wherein L5 is independently -NHC(O)-, –C(O)NH-,substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. Embodiment P175. The compound of one of Embodiments P127 to P173, wherein L5 is independently -NHC(O)-. Embodiment P176. The compound of one of Embodiments P127 to P173, wherein L5A is independently a bond or unsubstituted alkylene; L5B is independently a bond, -NHC(O)-, or unsubstituted arylene; L5C is independently a bond, unsubstituted alkylene, or unsubstituted arylene; L5D is independently a bond or unsubstituted alkylene; and L5E is independently a bond or -NHC(O)-. Embodiment P177. The compound of one of Embodiments P127 to P173, wherein L5A is independently a bond or unsubstituted C1-C8 alkylene; L5B is independently a bond, -NHC(O)-, or unsubstituted phenylene; L5C is independently a bond, unsubstituted C2-C8 alkynylene, or unsubstituted phenylene; L5D is independently a bond or unsubstituted C1-C8 alkylene; and L5E is independently a bond or -NHC(O)-. Embodiment P178. The compound of one of Embodiments P127 to P173, wherein Embodiment P179. The compound of one of Embodiments P127 to P173, wherein R1 is unsubstituted C1-C17 alkyl. Embodiment P180. The compound of one of Embodiments P127 to P173, wherein R1 is unsubstituted C11-C17 alkyl. Embodiment P181. The compound of one of Embodiments P127 to P173, wherein R1 is unsubstituted C13-C17 alkyl. Embodiment P182. The compound of one of Embodiments P127 to P173, wherein R1 is unsubstituted C14-C15 alkyl. Embodiment P183. The compound of one of Embodiments P127 to P173, wherein R1 is unsubstituted unbranched C1-C17 alkyl. Embodiment P184. The compound of one of Embodiments P127 to P173, wherein R1 is unsubstituted unbranched C11-C17 alkyl. Embodiment P185. The compound of one of Embodiments P127 to P173, wherein R1 is unsubstituted unbranched C13-C17 alkyl. Embodiment P186. The compound of one of Embodiments P127 to P173, wherein R1 is unsubstituted unbranched C14-C15 alkyl. Embodiment P187. The compound of one of Embodiments P127 to P173, wherein R1 is unsubstituted unbranched saturated C1-C17 alkyl. Embodiment P188. The compound of one of Embodiments P127 to P173, wherein R1 is unsubstituted unbranched saturated C11-C17 alkyl. Embodiment P189. The compound of one of Embodiments P127 to P173, wherein R1 is unsubstituted unbranched saturated C13-C17 alkyl. Embodiment P190. The compound of one of Embodiments P127 to P173, wherein R1 is unsubstituted unbranched saturated C14-C15 alkyl. Embodiment P191. The compound of one of Embodiments P127 to P190, wherein R2 is unsubstituted C1-C17 alkyl. Embodiment P192. The compound of one of Embodiments P127 to P190, wherein R2 is unsubstituted C11-C17 alkyl. Embodiment P193. The compound of one of Embodiments P127 to P190, wherein R2 is unsubstituted C13-C17 alkyl. Embodiment P194. The compound of one of Embodiments P127 to P190, wherein R2 is unsubstituted C14-C15 alkyl. Embodiment P195. The compound of one of Embodiments P127 to P190, wherein R2 is unsubstituted unbranched C1-C17 alkyl. Embodiment P196. The compound of one of Embodiments P127 to P190, wherein R2 is unsubstituted unbranched C11-C17 alkyl. Embodiment P197. The compound of one of Embodiments P127 to P190, wherein R2 is unsubstituted unbranched C13-C17 alkyl. Embodiment P198. The compound of one of Embodiments P127 to P190, wherein R2 is unsubstituted unbranched C14-C15 alkyl. Embodiment P199. The compound of one of Embodiments P127 to P190, wherein R2 is unsubstituted unbranched saturated C1-C17 alkyl. Embodiment P200. The compound of one of Embodiments P127 to P190, wherein R2 is unsubstituted unbranched saturated C11-C17 alkyl. Embodiment P201. The compound of one of Embodiments P127 to P190, wherein R2 is unsubstituted unbranched saturated C13-C17 alkyl. Embodiment P202. The compound of one of Embodiments P127 to P190, wherein R2 is unsubstituted unbranched saturated C14-C15 alkyl. Embodiment P203. The compound of any one of Embodiments P127 to P202, wherein the ligand is covalently linked to the antisense strand. Embodiment P204. The compound of any one of Embodiments P127 to P202, wherein the ligand is covalently linked to the sense strand. Embodiment P205. The compound of Embodiment P137, wherein -L3-L4- is , the phosphate group of -L3-L4- is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, , L5 is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C15 alkyl, and R2 is unsubstituted unbranched C15 alkyl. Embodiment P206. The compound of Embodiment P137, wherein -L3-L4- is , the phosphate group of -L3-L4- to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, , L5 is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C13 alkyl, and R2 is unsubstituted unbranched C13 alkyl. Embodiment P207. The compound of Embodiment P137, wherein the compound is selected from DT-000429, DT-000430, DT-000431, DT-000432, DT-000735, DT-000736, DT-000737, DT-000738, DT-000776, DT-000777, DT-000778, DT-000785, DT-000786, DT-000787, DT-000828, DT-000829, DT-000830, DT-000831, and DT-000832. Embodiment P208. The compound of Embodiment P137, wherein the compound is DT-000430. Embodiment P209. The compound of Embodiment P137, wherein the compound is DT-000432. Embodiment P210. The compound of Embodiment P137, wherein the compound is DT-000776 Embodiment P211. The compound of any one of Embodiments P1 to P210, wherein the compound is present as a pharmaceutical salt. Embodiment P212. The compound of Embodiment P211, wherein the salt is a sodium salt. Embodiment P213. The compound of any one of Embodiments P1 to P212, wherein the compound is present in a pharmaceutically acceptable diluent. Embodiment P214. The compound of Embodiment P213, wherein the pharmaceutically acceptable diluent is a sterile aqueous solution. Embodiment P215. The compound of Embodiment P214, wherein the sterile aqueous solution is a sterile saline solution. Embodiment P216. A pharmaceutical composition comprising the compound of any one of Embodiments P1 to P215. Embodiment P217. A method of inhibiting the expression of neural retina leucine zipper (NRL) mRNA in a cell, comprising contacting the cell with a compound of any one of Embodiments P1 to P215, thereby inhibiting the expression of NRL mRNA in the cell. Embodiment P218. The method of Embodiment P217, wherein the cell is a photoreceptor cell. Embodiment P219. The method of Embodiment P218, wherein the cell is in vitro. Embodiment P220. The method of Embodiment P218, wherein the cell is in vivo. Embodiment P221. A method of inhibiting the expression of neural retina leucine zipper (NRL) in a subject, comprising administering to the subject an effective amount of a compound of any one of Embodiments P1 to P215 or the pharmaceutical composition of Embodiment P216, thereby inhibiting the expression of neural retina leucine zipper (NRL) mRNA. Embodiment P222. A method of treating retinitis pigmentosa, comprising administering to a subject in need thereof an effective amount of a compound of any one of Embodiments P1 to P215 or the pharmaceutical composition of Embodiment P216. Embodiment P223. The method of Embodiment P221 or Embodiment P222, wherein prior to administration of the compound, the subject has been diagnosed as having retinitis pigmentosa. Embodiment P224. The method of Embodiment P223, wherein the subject is diagnosed as having retinitis pigmentosa by the presence of one or more of: a family history of retinitis pigmentosa; decreased visual acuity; abnormal retinal morphology; the presence of nyctalopia; visual field constriction; a reduced response to light stimulus; and retinal pigmentation abnormalities. Embodiment P225. The method of any Embodiments P221 to P224, wherein the administration is selected from intraocular administration and topical administration. Embodiment P226. The method of Embodiment P225, wherein the intraocular administration is subconjunctival administration, intravitreal administration, retrobulbar administration, or intracameral administration. Embodiment P227. The method of any one of Embodiments P221 to P226, wherein the administration improves or slows the progression of one or more indicators of retinitis pigmentosa in the subject, wherein the one or more indicators is selected from visual acuity, visual acuity, retinal morphology, nyctalopia, visual field constriction, response to a light stimulus, and retinal pigmentation. Embodiment P228. The method of Embodiment P227, wherein response to a light stimulus is measured by electroretinography. Embodiment P229. The method of any one of Embodiments P221 to P228, comprising administering at least one additional therapy to the subject. Embodiment P230. Use of the compound of any one of Embodiments P1 to P215 in therapy. Embodiment P231. Use of the compound of any one of Embodiments P1 to P215 for the treatment of retinitis pigmentosa. Embodiment P232. Use of the pharmaceutical composition of Embodiment P216 for the treatment of retinitis pigmentosa. Embodiment P233. The compound of Embodiment P27, wherein the nucleotide sequence of the antisense strand comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or 21 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 213, 215, 217, 224, 241, 226, 228, and 230. Embodiment P234. The compound of Embodiment P233, wherein the nucleotide sequence of the antisense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236. Embodiment P235. The compound of Embodiment P233, wherein the antisense strand is 21 nucleotides in length and the nucleotide sequence of the antisense strand is identical to a nucleotide sequence selected from SEQ ID NO: 213, 215, 217, 224, 241, 226, 228, and 230. Embodiment P236. The compound of Embodiment P233, wherein the antisense strand is 23 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 213, 215, 217, 224, 241, 226, 228, and 230, and wherein the nucleotide sequence of the antisense strand is 100% complementary to 23 contiguous nucleotides of SEQ ID NO: 1. Embodiment P237. The compound of any one of Embodiments P233 to P236, wherein the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236. Embodiment P238. The compound of any one of Embodiments P233 to P236, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236. Embodiment P239. The compound of any one of Embodiments P233 to P236, wherein the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236. Embodiment P240. The compound of any one of Embodiments P233 to P236, wherein the sense strand is 21 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 212, 214, 216, 223, 218, 222, 223, 224, 245, 219, 264, 265, 220, 240, 225, 227, 231, 233, 266, 267, 221, 242, 234, 243, 235, 244, and 236, and wherein the nucleotide sequence of the sense strand is identical to 21 contiguous nucleotides of SEQ ID NO: 1. Embodiment P241. The compound of any one of Embodiments P45 to P49, wherein the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 268 and 269. Embodiment P242. The compound of any one of Embodiments P45 to P49, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 268 and 269. Embodiment P243. The compound of any one of Embodiments P45 to P49, wherein the sense strand is 19 nucleotides in length and comprises a nucleotide sequence that is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 268 and 269. Embodiment P244. The compound of any one of Embodiments P45 to P49, wherein the sense strand is 21 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 268 and 269, and wherein the nucleotide sequence of the sense strand is identical to a 21 contiguous nucleotides of SEQ ID NO: 1. Embodiment P245. The compound of any one of Embodiments P63 to P67, wherein the nucleotide sequence of the sense strand comprises 19 contiguous nucleotides of SEQ ID NO: 237. Embodiment P246. The compound of any one of Embodiments P63 to P67, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to the nucleotide sequence of SEQ ID NO: 237. Embodiment P247. The compound of any one of Embodiments P63 to P67, wherein the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of the nucleotide sequence of SEQ ID NO: 237. Embodiment P248. The compound of any one of Embodiments P63 to P67, wherein the sense strand is 21 nucleotides in length and comprises nucleotides 1 to 19 of the nucleotide sequence of SEQ ID NO: 237, and wherein the nucleotide sequence of the sense strand is identical to 21 contiguous nucleotides of SEQ ID NO: 1. Embodiment P249. The compound of any one of Embodiments P72 to P76, wherein the sense strand comprises 19 contiguous nucleotides of a nucleotide sequence selected from SEQ ID NO: 238, 270, 271, 272, and 273. Embodiment P250. The compound of any one of Embodiments P72 to P76, wherein the sense strand is 21 nucleotides in length and the nucleotide sequence of the sense strand is identical to a nucleotide sequence selected from SEQ ID NO: 238, 270, 271, 272, and 273. Embodiment P251. The compound of any one of Embodiments P72 to P76, wherein the sense strand is 19 nucleotides in length and the nucleotide sequence of the sense strand is identical to nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 238, 270, 271, 272, and 273. Embodiment P252. The compound of any one of Embodiments P72 to P76, wherein the sense strand is 21 nucleotides in length and comprises nucleotides 1 to 19 of a nucleotide sequence selected from SEQ ID NO: 238, 270, 271, 272, and 273, and wherein the nucleotide sequence of the sense strand is identical to 21 contiguous nucleotides of SEQ ID NO: 1. Embodiment P253. The compound of any one of Embodiments P233 to P252, wherein the nucleotide sequence of the antisense strand is at least 95% complementary to SEQ ID NO: 1. Embodiment P254. The compound of any one of Embodiments P233 to P252, wherein the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1. Embodiment P255. The compound of any one of Embodiments P233 to P254, wherein the antisense strand and the sense strand are not covalently linked. Embodiment P256. The compound of any one of Embodiments P233 to P255, wherein the hybridization of the antisense strand to the sense strand forms at least one blunt end. Embodiment P257. The compound of Embodiment P256, wherein the hybridization of the antisense strand to the sense strand forms a blunt end at each terminus of the compound. Embodiment P258. The compound of any one of Embodiments P233 to P256, wherein at least one strand comprises a 3’ nucleotide overhang of one to five nucleotides. Embodiment P259. The compound of Embodiment P258, wherein the sense strand comprises the 3’ nucleotide overhang. Embodiment P260. The compound of Embodiment P258, wherein the antisense strand comprises the 3’ nucleotide overhang. Embodiment P261. The compound of Embodiment P258, wherein each of the sense strand and the antisense strand comprises a 3’ nucleotide overhang of one to five nucleotides. Embodiment P262. The compound of Embodiment P260 or P261, wherein each nucleotide of the 3’ nucleotide overhang of the antisense strand is complementary to SEQ ID NO: 1. Embodiment P263. The compound of Embodiment P260 or P261, wherein each nucleotide of the 3’ nucleotide overhang of the antisense strand is not complementary to SEQ ID NO: 1 Embodiment P264. The compound of any one of Embodiments P258 to P263, wherein each nucleotide of the 3’ nucleotide overhang is a deoxythymidine. Embodiment P265. The compound of any one of Embodiments P258 to P264, wherein the 3’ nucleotide overhang is two nucleotides in length. Embodiment P266. The compound of any one of Embodiments P233 to P265, wherein at least one nucleotide of the antisense strand is a modified nucleotide. Embodiment P267. The compound of any one of Embodiments P233 to P266, wherein at least one nucleotide of the sense strand is a modified nucleotide. Embodiment P268. The compound of any one of Embodiments P233 to P267, wherein each nucleotide of the antisense strand forming the double-stranded region is a modified nucleotide. Embodiment P269. The compound of any one of Embodiments P233 to P268, wherein each nucleotide of the sense strand forming the double-stranded region is a modified nucleotide. Embodiment P270. The compound of any one of Embodiments P266 to P269, wherein the modified nucleotide comprises one or more of a modified sugar moiety, a modified internucleotide linkage, and a 5’-terminal modified phosphate group. Embodiment P271. The compound of Embodiment P270, wherein the modified nucleotide comprising a modified sugar moiety is selected from a 2’-fluoro nucleotide, a 2’- O-methyl nucleotide, a 2’-O-methoxyethyl nucleotide, and a bicyclic sugar nucleotide. Embodiment P272. The compound of Embodiment P270, wherein the modified internucleotide linkage is a phosphorothioate internucleotide linkage. Embodiment P273. The compound of Embodiment P272, wherein the first two internucleotide linkages at the 5’ terminus of the sense strand and the last two internucleotide linkages at the 3’ terminus of the sense strand are phosphorothioate internucleotide linkages. Embodiment P274. The compound of Embodiment P273, wherein the first two internucleotide linkages at the 5’ terminus of the antisense strand and the last two internucleotide linkages at the 3’ terminus of the antisense strand are phosphorothioate internucleotide linkages. Embodiment P275. The compound of Embodiment P271, wherein the covalent linkage of the bicyclic sugar is selected from a 4’-CH(CH3)-O-2’ linkage, a 4'-(CH2)2-O-2' linkage, a 4'-CH(CH2-OMe)-O-2' linkage, 4’-CH2-N(CH3)-O-2’ linkage, and 4’-CH2-N(H)- O-2’ linkage. Embodiment P276. The compound of Embodiment P270, wherein the 5’-terminal modified phosphate group is a 5’-(E)-vinylphosphonate. Embodiment P277. The compound of any one of Embodiments P233 to P276, wherein the antisense strand is 21 nucleotides in length, and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O- methylnucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-flouronucleotides, and nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P278. The compound of any one of Embodiments P233 to P276, wherein the antisense strand is 19 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O- methylnucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-flouronucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P279. The compound of Embodiment P277 or P278, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides, and nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P280. The compound of Embodiment P277 or P278, wherein the sense strand is 19 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoro nucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P281. The compound of any one of Embodiments P233 to P276, wherein the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methylnucleotides and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’- flouronucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P282. The compound of Embodiment P281, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P283. The compound of Embodiment P281, wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta- D-deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P284. The compound of Embodiment P281, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P285. The compound of any one of Embodiments P233 to P276, wherein the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methylnucleotides and nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’- flouronucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P286. The compound of Embodiment P285, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P287. The compound of Embodiment P285, wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta-D- deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P288. The compound of any one of Embodiments P233 to P276, wherein the antisense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, 21, 22, and 23 are 2’-O-methylnucleotides and nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2’- flouronucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P289. The compound of Embodiment P288, wherein the sense strand is 21 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-O-methyl nucleotides; the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P290. The compound of Embodiment P288, wherein the sense strand is 23 nucleotides in length and wherein counting from the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2’-fluoronucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2’-O-methyl nucleotides, nucleotides 22 and 23 are beta-D- deoxynucleotides, the first two internucleotide linkages at the 5’ terminus and the last two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. Embodiment P291. The compound of any one of Embodiments P233 to P290, wherein the compound comprises a ligand covalently linked to the double-stranded nucleic acid. Embodiment P292. The compound of Embodiment P291, wherein the compound has the structure: wherein A is the double-stranded nucleic acid; wherein t is an integer from 1 to 5; L3 and L4 are independently a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, -C(O)N(R24)-, -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O-P(S)(NR23R24)-N-, -O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; L5 is -L5A-L5B-L5C-L5D-L5E-; L6 is -L6A-L6B-L6C-L6D-L6E-; R1 and R2 are independently unsubstituted C1-C25 alkyl, wherein at least one of R1 and R2 is unsubstituted C9-C19 alkyl; R3 is hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, –N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L5A, L5B, L5C, L5D, L5E, L6A, L6B, L6C, L6D, and L6E are independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, –C(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; and each R23, R24 and R25 is independently hydrogen or unsubstituted C1-C10 alkyl. Embodiment P293. The compound of Embodiment P292, wherein t is 1. Embodiment P294. The compound of Embodiment P292, wherein t is 2. Embodiment P295. The compound of Embodiment P292, wherein t is 3. Embodiment P296. The compound of any one of Embodiments P292 to P295, wherein A is the sense strand. Embodiment P297. The compound of any one of Embodiments P292 to P296, wherein A is the antisense strand. Embodiment P298. The compound of one of Embodiments P292 to P297, wherein each of R23, R24 and R25 is independently hydrogen or unsubstituted C1-C3 alkyl. Embodiment P299. The compound of one of Embodiments P292 to P298, wherein one L3 is attached to a 3’ carbon of a nucleotide. Embodiment P300. The compound of Embodiment P299, wherein the 3’ carbon is the 3’ carbon of a 3’ terminal nucleotide. Embodiment P301. The compound of one of Embodiments P292 to P300, wherein one L3 is attached to a 5’ carbon of a nucleotide. Embodiment P302. The compound of Embodiment P301, wherein the 5’ carbon is the 5’ carbon of a 5’ terminal nucleotide. Embodiment P303. The compound of one of Embodiments P292 to P302, wherein one L3 is attached to a 2’ carbon of a nucleotide. Embodiment P304. The compound of one of Embodiments P292 to P303, wherein L3 and L4 are independently a bond, NH, O, C(O), C(O)O, OC(O), OPO2O, -O-P(O)(S)-O-, -O-P(O)(CH3)-O-, -O-P(S)(CH3)-O-, -O-P(O)(N(CH3)2)-N-, -O-P(O)(N(CH3)2)-O-, -O-P(S)(N(CH3)2)-N-, -O-P(S)(N(CH3)2)-O-, - P(O)(N(CH3)2)-N-, -P(O)(N(CH3)2)-O-, -P(S)(N(CH3)2)-N-, -P(S)(N(CH3)2)-O-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. Embodiment P305. The compound of one of Embodiments P292 to P304, wherein L3 is independently . Embodiment P306. The compound of one of Embodiments P292 to P304, wherein L3 is independently OPO2O or –OP(O)(S)O. Embodiment P307. The compound of one of Embodiments P292 to P304, wherein L3 is independently –O-. Embodiment P308. The compound of any one of Embodiments P292 to P304, wherein L3 is independently -C(O)-. Embodiment P309. The compound of any one of Embodiments P292 to P304, wherein L3 is independently -O-P(O)(N(CH3)2)-N-. Embodiment P310. The compound of one of Embodiments P292 to P309, wherein L4 is independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. Embodiment P311. The compound of one of Embodiments P292 to P310, wherein L4 is independently –L7-NH-C(O)- or –L7-C(O)-NH-, wherein L7 is substituted or unsubstituted alkylene. Embodiment P312. The compound of one of Embodiments P292 to P311, wherein L4 is independently . Embodiment P313. The compound of one of Embodiments P292 to P311, wherein L4 is independently . Embodiment P314. The compound of one of Embodiments P292 to P313, wherein –L3-L4- is independently –O-L7-NH-C(O)- or –O-L7-C(O)-NH-, wherein L7 is independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene. Embodiment P315. The compound of Embodiment P314, wherein –L3-L4- is independently –O-L7-NH-C(O)-, wherein L7 is independently substituted or unsubstituted C5- C8 alkylene. Embodiment P316. The compound of Embodiment P315, wherein –L3-L4- is . Embodiment P317. The compound of one of Embodiments P292 to P304, wherein –L3-L4- is independently OPO2OL7-NH-C(O)-, OP(O)(S)OL7-NH-C(O)-, -OPO2OL7-C(O)- NH-or –OP(O)(S)-OL7-C(O)-NH-, wherein L7 is independently substituted or unsubstituted alkylene. Embodiment P318. The compound of Embodiment P317, wherein –L3-L4- is independently OPO2OL7-NH-C(O)- or –OP(O)(S)OL7-NH-C(O)-, wherein L7 is independently substituted or unsubstituted C5-C8 alkylene. Embodiment P319. The compound of Embodiment P318, wherein –L3-L4- is Embodiment P320. The compound of Embodiment P319, wherein an –L3-L4- is attached to the 3’ carbon of a 3’ terminal nucleotide. Embodiment P321. The compound of Embodiment P319, wherein an –L3-L4- is terminal nucleotide. Embodiment P322. The compound of Embodiment P319, wherein an –L3-L4- is attached to a 2’ carbon. Embodiment P323. The compound of one of Embodiments P292 to P322, wherein R3 is independently hydrogen. Embodiment P324. The compound of one of Embodiments P292 to P323, wherein L6 is independently NHC(O), –C(O)NH-,substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. Embodiment P325. The compound of Embodiment P324, wherein L6 is independently -NHC(O)-. Embodiment P326. The compound of Embodiment P324, wherein L6A is independently a bond or unsubstituted alkylene; L6B is independently a bond, -NHC(O)-, or unsubstituted arylene; L6C is independently a bond, unsubstituted alkylene, or unsubstituted arylene; L6D is independently a bond or unsubstituted alkylene; and L6E is independently a bond or -NHC(O)-. Embodiment P327. The compound of Embodiment P324, wherein L6A is independently a bond or unsubstituted C1-C8 alkylene; L6B is independently a bond, -NHC(O)-, or unsubstituted phenylene; L6C is independently a bond, unsubstituted C2-C8 alkynylene, or unsubstituted phenylene; L6D is independently a bond or unsubstituted C1-C8 alkylene; and L6E is independently a bond or -NHC(O)-. Embodiment P328. The compound of one of Embodiments P292 to P323, wherein Embodiment P329. The compound of one of Embodiments P292 to P328, wherein L5 is independently NHC(O), –C(O)NH-,substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. Embodiment P330. The compound of one of Embodiments P292 to P328, wherein L5 is independently -NHC(O)-. Embodiment P331. The compound of one of Embodiments P292 to P328, wherein L5A is independently a bond or unsubstituted alkylene; L5B is independently a bond, -NHC(O)-, or unsubstituted arylene; L5C is independently a bond, unsubstituted alkylene, or unsubstituted arylene; L5D is independently a bond or unsubstituted alkylene; and L5E is independently a bond or -NHC(O)-. Embodiment P332. The compound of one of Embodiments P292 to P328, wherein L5A is independently a bond or unsubstituted C1-C8 alkylene; L5B is independently a bond, -NHC(O)-, or unsubstituted phenylene; L5C is independently a bond, unsubstituted C2-C8 alkynylene, or unsubstituted phenylene; L5D is independently a bond or unsubstituted C1-C8 alkylene; and L5E is independently a bond or -NHC(O)-. Embodiment P333. The compound of one of Embodiments P292 to P328, wherein Embodiment P334. The compound of one of Embodiments P292 to P333, wherein R1 is unsubstituted C1-C17 alkyl. Embodiment P335. The compound of one of Embodiments P292 to P333, wherein R1 is unsubstituted C11-C17 alkyl. Embodiment P336. The compound of one of Embodiments P292 to P333, wherein R1 is unsubstituted C13-C17 alkyl. Embodiment P337. The compound of one of Embodiments P292 to P333, wherein R1 is unsubstituted C14-C15 alkyl. Embodiment P338. The compound of one of Embodiments P292 to P333, wherein R1 is unsubstituted unbranched C1-C17 alkyl. Embodiment P339. The compound of one of Embodiments P292 to P333, wherein R1 is unsubstituted unbranched C11-C17 alkyl. Embodiment P340. The compound of one of Embodiments P292 to P333, wherein R1 is unsubstituted unbranched C13-C17 alkyl. Embodiment P341. The compound of one of Embodiments P292 to P333, wherein R1 is unsubstituted unbranched C14-C15 alkyl. Embodiment P342. The compound of one of Embodiments P292 to P333, wherein R1 is unsubstituted unbranched saturated C1-C17 alkyl. Embodiment P343. The compound of one of Embodiments P292 to P333, wherein R1 is unsubstituted unbranched saturated C11-C17 alkyl. Embodiment P344. The compound of one of Embodiments P292 to P333, wherein R1 is unsubstituted unbranched saturated C13-C17 alkyl. Embodiment P345. The compound of one of Embodiments P292 to P333, wherein R1 is unsubstituted unbranched saturated C14-C15 alkyl. Embodiment P346. The compound of one of Embodiments P292 to P345, wherein R2 is unsubstituted C1-C17 alkyl. Embodiment P347. The compound of one of Embodiments P292 to P345, wherein R2 is unsubstituted C11-C17 alkyl. Embodiment P348. The compound of one of Embodiments P292 to P345, wherein R2 is unsubstituted C13-C17 alkyl. Embodiment P349. The compound of one of Embodiments P292 to P345, wherein R2 is unsubstituted C14-C15 alkyl. Embodiment P350. The compound of one of Embodiments P292 to P345, wherein R2 is unsubstituted unbranched C1-C17 alkyl. Embodiment P351. The compound of one of Embodiments P292 to P345, wherein R2 is unsubstituted unbranched C11-C17 alkyl. Embodiment P352. The compound of one of Embodiments P292 to P345, wherein R2 is unsubstituted unbranched C13-C17 alkyl. Embodiment P353. The compound of one of Embodiments P292 to P345, wherein R2 is unsubstituted unbranched C14-C15 alkyl. Embodiment P354. The compound of one of Embodiments P292 to P345, wherein R2 is unsubstituted unbranched saturated C1-C17 alkyl. Embodiment P355. The compound of one of Embodiments P292 to P345, wherein R2 is unsubstituted unbranched saturated C11-C17 alkyl. Embodiment P356. The compound of one of Embodiments P292 to P345, wherein R2 is unsubstituted unbranched saturated C13-C17 alkyl. Embodiment P357. The compound of one of Embodiments P292 to P345, wherein R2 is unsubstituted unbranched saturated C14-C15 alkyl. Embodiment P358. The compound of any one of Embodiments P292 to P357, wherein the ligand is covalently linked to the antisense strand. Embodiment P359. The compound of any one of Embodiments P292 to P358, wherein the ligand is covalently linked to the sense strand. Embodiment P360. The compound of Embodiment P292, wherein -L3-L4- , the phosphate group of -L3-L4- is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, , L5 is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C15 alkyl, and R2 is unsubstituted unbranched C15 alkyl. Embodiment P361. The compound of Embodiment P292, wherein -L3-L4- is , the phosphate group of -L3-L4- to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, , L5 is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C13 alkyl, and and R2 is unsubstituted unbranched C13 alkyl. Embodiment P362. The compound of Embodiment P292, wherein the compound is selected from DT-001373, DT-001374, DT-001375, and DT-001386. Embodiment P363. The compound of Embodiment P292, wherein the compound is DT-001373. Embodiment P364. The compound of Embodiment P292, wherein the compound is DT-001374. Embodiment P365. The compound of Embodiment P292, wherein the compound is DT-001375. Embodiment P366. The compound of Embodiment P292, wherein the compound is DT-001386. Embodiment P367. The compound of any one of Embodiments P233 to P366, wherein the compound is present as a pharmaceutical salt. Embodiment P368. The compound of Embodiment P367, wherein the salt is a sodium salt. Embodiment P369. The compound of any one of Embodiments P233 to P368, wherein the compound is present in a pharmaceutically acceptable diluent. Embodiment P370. The compound of Embodiment P369, wherein the pharmaceutically acceptable diluent is a sterile aqueous solution. Embodiment P371. The compound of Embodiment P370, wherein the sterile aqueous solution is a sterile saline solution. Embodiment P372. A pharmaceutical composition comprising the compound of any one of Embodiments P233 to P371. Embodiment P373. A method of inhibiting the expression of neural retina leucine zipper (NRL) mRNA in a cell, comprising contacting the cell with a compound of any one of Embodiments P233 to P371, thereby inhibiting the expression of NRL mRNA in the cell. Embodiment P374. The method of Embodiment P373, wherein the cell is a photoreceptor cell. Embodiment P375. The method of Embodiment P373, wherein the cell is in vitro. Embodiment P376. The method of Embodiment P373, wherein the cell is in vivo. Embodiment P377. A method of inhibiting the expression of neural retina leucine zipper (NRL) in a subject, comprising administering to the subject an effective amount of a compound of any one of Embodiments P233 to P371 or the pharmaceutical composition of Embodiment P372, thereby inhibiting the expression of neural retina leucine zipper (NRL) mRNA. Embodiment P378. A method of treating retinitis pigmentosa, comprising administering to a subject in need thereof an effective amount of a compound of any one of Embodiments P233 to P371 or the pharmaceutical composition of Embodiment P372. Embodiment P379. The method of Embodiment P377 or P378, wherein prior to administration of the compound, the subject has been diagnosed as having retinitis pigmentosa. Embodiment P380. The method of Embodiment P379, wherein the subject is diagnosed as having retinitis pigmentosa by the presence of one or more of: a family history of retinitis pigmentosa; decreased visual acuity; abnormal retinal morphology; the presence of nyctalopia; visual field constriction; a reduced response to light stimulus; and retinal pigmentation abnormalities. Embodiment P381. The method of any one of Embodiments P377 to P380, wherein the administration is selected from intraocular administration and topical administration. Embodiment P382. The method of Embodiment P381, wherein the intraocular administration is subconjunctival administration, intravitreal administration, retrobulbar administration, or intracameral administration. Embodiment P383. The method of any one of Embodiments P377 to P382, wherein the administration improves or slows the progression of one or more indicators of retinitis pigmentosa in the subject, wherein the one or more indicators is selected from visual acuity, visual acuity, retinal morphology, nyctalopia, visual field constriction, response to a light stimulus, and retinal pigmentation. Embodiment P384. The method of Embodiment P383, wherein response to a light stimulus is measured by electroretinography. Embodiment P385. The method of any one of Embodiments P377 to P384, comprising administering at least one additional therapy to the subject. Embodiment P386. Use of the compound of any one of Embodiments P233 to P371 in therapy. Embodiment P387. Use of the compound of any one of Embodiments P233 to P371 for the treatment of retinitis pigmentosa. Embodiment P388. Use of the pharmaceutical composition of Embodiment P372 for the treatment of retinitis pigmentosa. Additional embodiments Embodiment Q1. A compound comprising an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein each of the antisense strand and sense strands is 15 to 25 nucleotides in length, the nucleotide sequence of the antisense strand is at least 90% complementary to the nucleotide sequence of the NRL mRNA (SEQ ID NO: 1), and the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand. Embodiment Q2. The compound of Embodiment Q1, wherein each of the antisense strand and sense strands is 15 to 25 nucleotides in length, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 contiguous nucleotides of any one of nucleotides 501 to 563 of SEQ ID NO: 1, nucleotides 602 to 626 of SEQ ID NO: 1, nucleotides 623 to 654 of SEQ ID NO: 1, nucleotides 684 to 710 of SEQ ID NO: 1, nucleotides 741 to 765 of SEQ ID NO: 1, nucleotides 759 to 777 of SEQ ID NO: 1, nucleotides 882 to 909 of SEQ ID NO: 1, or nucleotides 1111 to 1133 of SEQ ID NO: 1, and the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand. Embodiment Q3. The compound of Embodiment Q1 or Q2, wherein i. the antisense strand is 19 to 21 nucleotides in length; or ii. the antisense strand is 21 to 23 nucleotides in length. Embodiment Q4. The compound of any one of Embodimens Q1 to Q3, wherein i. the sense strand is 17 to 23 nucleotides in length; ii. the sense strand is 19 to 21 nucleotides in length; or iii. the sense strand is 21 to 23 nucleotides in length. Embodiment Q5. The compound of any one of Embodiments Q1 to Q4, wherein i. the double-stranded region is 19 nucleotide pairs in length; ii. the double-stranded region is 20 nucleotide pairs in length; or iii. the double-stranded region is 21 nucleotide pairs in length. Embodiment Q6. The compound of any one of Embodiments Q1 to Q5, wherein the nucleotide sequence of the sense strand has no more than one mismatch to the nucleotide sequence of the antisense strand. Embodiment Q7. The compound of any one of Embodiments Q1 to Q6, wherein the nucleotide sequence of the sense strand has no mismatches to the nucleotide sequence of the antisense strand. Embodiment Q8. The compound of any one of Embodiments Q1 to Q7, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1. Embodiment Q9. The compound of any one of Embodiments Q1 to Q7, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1. Embodiment Q10. The compound of any one of Embodiments Q1 to Q7, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1. Embodiment Q11. The compound of any one of Embodiments Q1 to Q7, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1. Embodiment Q12. The compound of any one of Embodiments Q1 to Q7, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1. Embodiment Q13. The compound of any one of Embodiments Q1 to Q7, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, or 19 contiguous nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1. Embodiment Q14. The compound of any one of Embodiments Q1 to Q7, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or 23 contiguous nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1. Embodiment Q15. The compound of any one of Embodiments Q1 to Q14, wherein the antisense strand and the sense strand are not covalently linked. Embodiment Q16. The compound of any one of Embodiments Q1 to Q15, wherein at least one strand comprises a 3’ nucleotide overhang of one to five nucleotides. Embodiment Q17. The compound of Embodiment Q16, wherein the sense strand comprises the 3’ nucleotide overhang. Embodiment Q18. The compound of Embodiment Q16, wherein the antisense strand comprises the 3’ nucleotide overhang. Embodiment Q19. The compound of any one of Embodiments Q16 to Q18, wherein each nucleotide of the 3’ nucleotide overhang of the antisense strand is complementary to SEQ ID NO: 1. Embodiment Q20. The compound of any one of Embodiments Q16 to Q19, wherein the 3’ nucleotide overhang is two nucleotides in length. Embodiment Q21. The compound of any one of Embodiments Q1 to Q20, wherein each nucleotide of the antisense strand forming the double-stranded region is a modified nucleotide. Embodiment Q22. The compound of any one of Embodiments Q1 to Q21, wherein each nucleotide of the sense strand forming the double-stranded region is a modified nucleotide. Embodiment Q23. The compound of Embodiment Q21 or Q22, wherein the modified nucleotide comprises one or more of a modified sugar moiety, a modified internucleotide linkage, and a 5’-terminal modified phosphate group. Embodiment Q24. The compound of Embodiment Q23, wherein the modified nucleotide comprising a modified sugar moiety is selected from a 2’-fluoro nucleotide, a 2’-O-methyl nucleotide, a 2’-O-methoxyethyl nucleotide, and a bicyclic sugar nucleotide. Embodiment Q25. The compound of Embodiment Q23, wherein the modified internucleotide linkage is a phosphorothioate internucleotide linkage. Embodiment Q26. The compound of Embodiment Q25, wherein the first two internucleotide linkages at the 5’ terminus of the sense strand and the last two internucleotide linkages at the 3’ terminus of the sense strand are phosphorothioate internucleotide linkages. Embodiment Q27. The compound of Embodiment Q26, wherein the first two internucleotide linkages at the 5’ terminus of the antisense strand and the last two internucleotide linkages at the 3’ terminus of the antisense strand are phosphorothioate internucleotide linkages. Embodiment Q28. The compound of any one of Embodiments Q1 to Q27, wherein the compound comprises a ligand covalently linked to the double-stranded nucleic acid. Embodiment Q29. The compound of Embodiment Q28, wherein the compound has the structure: wherein A is the double-stranded nucleic acid; wherein t is an integer from 1 to 5; L3 and L4 are independently a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, -C(O)N(R24)-, -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O-P(S)(NR23R24)-N-, -O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; L5 is -L5A-L5B-L5C-L5D-L5E-; L6 is -L6A-L6B-L6C-L6D-L6E-; R1 and R2 are independently unsubstituted C1-C25 alkyl, wherein at least one of R1 and R2 is unsubstituted C9-C19 alkyl; R3 is hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, –N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L5A, L5B, L5C, L5D, L5E, L6A, L6B, L6C, L6D, and L6E are independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, –C(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; and each R23, R24 and R25 is independently hydrogen or unsubstituted C1-C10 alkyl. Embodiment Q30. The compound of Embodiment Q29, wherein (i) t is 1; (ii) t is 2; or (iii) t is 3. Embodiment Q31. The compound of Embodiment Q29, wherein A is the sense strand of the double-stranded nucleic acid. Embodiment Q32. The compound of Embodiment Q31, wherein -L3-L4- the phosphate group of -L3-L4- is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, , L5 is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C15 alkyl, and R2 is unsubstituted unbranched C15 alkyl. Embodiment Q33. The compound of Embodiment Q31, wherein -L3-L4- is , the phosphate group of -L3-L4- to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, , L5 is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C13 alkyl, and and R2 is unsubstituted unbranched C13 alkyl. Embodiment Q34. The compound of Embodiment Q31, wherein the compound is selected from DT-000429, DT-000430, DT-000431, DT-000432, DT-000735, DT- 000736, DT-000737, DT-000738, DT-000776, DT-000777, DT-000778, DT-000785, DT-000786, DT-000787, DT-000828, DT-000829, DT-000830, DT-000831, DT-000832, DT-001373, DT-001374, DT-001375, and DT-001386. Embodiment Q35. The compound of Embodiment Q31, wherein the compound is DT-000430. Embodiment Q36. The compound of Embodiment Q31, wherein the compound is DT-000432. Embodiment Q37. The compound of Embodiment Q31, wherein the compound is DT-000776. Embodiment Q38. The compound of Embodiment Q31, wherein the compound is DT-001373. Embodiment Q39. The compound of Embodiment Q31, wherein the compound is DT-001374. Embodiment Q40. The compound of Embodiment Q31, wherein the compound is DT-001375. Embodiment Q41. The compound of Embodiment Q31, wherein the compound is DT-001386. Embodiment Q42. The compound of any one of Embodiments Q1 to Q41, wherein the compound is present as a pharmaceutical salt. Embodiment Q43. The compound of Embodiment Q42, wherein the salt is a sodium salt. Embodiment Q44. The compound of any one of Embodiments Q1 to Q43, wherein the compound is present in a pharmaceutically acceptable diluent. Embodiment Q45. The compound of Embodiment Q44, wherein the pharmaceutically acceptable diluent is a sterile aqueous solution. Embodiment Q46. The compound of Embodiment Q45, wherein the sterile aqueous solution is a sterile saline solution. Embodiment Q47. A pharmaceutical composition comprising the compound of any one of Embodiments Q1 to Q46. Embodiment Q48. A method of inhibiting the expression of neural retina leucine zipper (NRL) mRNA in a cell, comprising contacting the cell with a compound of any one of Embodiments Q1 to Q46, thereby inhibiting the expression of NRL mRNA in the cell. Embodiment Q49. The method of Embodiment Q48, wherein the cell is a photoreceptor cell. Embodiment Q50. The method of Embodiment Q49, wherein the cell is in vitro. Embodiment Q51. The method of Embodiment Q49, wherein the cell is in vivo. Embodiment Q52. A method of inhibiting the expression of neural retina leucine zipper (NRL) in a subject, comprising administering to the subject an effective amount of a compound of any one of Embodiments Q1 to Q46 or the pharmaceutical composition of Embodiment Q47, thereby inhibiting the expression of neural retina leucine zipper (NRL) mRNA. Embodiment Q53. A method of treating retinitis pigmentosa, comprising administering to a subject in need thereof an effective amount of a compound of any one of Embodiments Q1 to Q46 or the pharmaceutical composition of Embodiment Q47. Embodiment Q54. The method of Embodiment Q52 or Q53, wherein prior to administration of the compound, the subject has been diagnosed as having retinitis pigmentosa. Embodiment Q55. The method of Embodiment Q54, wherein the subject is diagnosed as having retinitis pigmentosa by the presence of one or more of: a family history of retinitis pigmentosa; decreased visual acuity; abnormal retinal morphology; the presence of nyctalopia; visual field constriction; a reduced response to light stimulus; and retinal pigmentation abnormalities. Embodiment Q56. The method of any one of Embodiments Q52 to Q55, wherein the administration is selected from intraocular administration and topical administration. Embodiment Q57. The method of Embodiment Q56, wherein the intraocular administration is subconjunctival administration, intravitreal administration, retrobulbar administration, or intracameral administration. Embodiment Q58. The method of any one of Embodiments Q52 to Q57, wherein the administration improves or slows the progression of one or more indicators of retinitis pigmentosa in the subject, wherein the one or more indicators is selected from visual acuity, visual acuity, retinal morphology, nyctalopia, visual field constriction, response to a light stimulus, and retinal pigmentation. Embodiment Q59. The method of Embodiment Q58, wherein response to a light stimulus is measured by electroretinography. Embodiment Q60. The method of any one of Embodiments Q52 to Q59, comprising administering at least one additional therapy to the subject. Embodiment Q61. Use of the compound of any one of Embodiments Q1 to Q46 in therapy. Embodiment Q62. Use of the compound of any one of Embodiments Q1 to Q46 for the treatment of retinitis pigmentosa. Embodiment Q63. Use of the pharmaceutical composition of Embodiment Q47 for the treatment of retinitis pigmentosa. Examples The following examples are presented to more fully illustrate some embodiments of the invention. They should not be construed, however, as limiting the scope of the invention. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the embodiments as described and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure and skill in the art, is able to prepare and use the invention without exhaustive examples.
Example 1: Conjugation of Uptake Motifs to Oligonucleotides Scheme I: Conjugation of Uptake Motifs to the 3’ Carbon of the 3’ Terminal Nucleotide of an Scheme I above illustrates the preparation of an oligonucleotide conjugated with a lipid moiety at the 3’ terminus of the oligonucleotide, i.e. at the 3’ carbon of the terminal 3’ nucleotide. In summary, 3’-amino CPG beads I-1 (Glen Research, Catalog No.20-2958) modified with the DMT and Fmoc-protected C7 linker illustrated above were treated with 20% piperidine/DMF to afford Fmoc-deprotected amino C7 CPG beads I-2. Lipid motif DTx-01-08 was then coupled to I-2 using HATU and DIEA in DMF to produce lipid-loaded CPG beads I-3, which were treated by 3% dichloroacetic acid (DCA) in DCM to remove the DMT protecting group and afford I-4. Oligonucleotide synthesis was accomplished via standard phosphoramidite chemistry and yielded oligonucleotide-bounded CPG beads I-5. At this point, if applicable, beads I-5 containing methyl ester-protected lipid motifs (e.g., DTx-01-07-OMe, DTx-01-09-OMe) were saponified to their respective carboxylic acid using 0.5 M LiOH in 3:1 v/v methanol/water. Subsequent treatment of I-5 with AMA [ammonium hydroxide (28%)/methylamine (40%) (1:1, v/v)] cleaved the DTx-01-08-conjugated oligonucleotide from the beads. The conjugated oligonucleotide was then purified by RP-HPLC and characterized by MALDI-TOF MS using the [M+H] peak.
Scheme II: Conjugation of Uptake Motifs to both the 3’ and 5’ Termini of an Oligonucleotide Scheme II above illustrates the preparation of a sense strand of a double-stranded oligonucleotide conjugated with a fatty-acid uptake motif at each of the 5’ and 3’ termini. In summary, 3’-amino CPG beads II-1 (Glen Research, Catalog No.20-2958) modified with the DMT and Fmoc-protected C7 linker illustrated above were treated with 20% piperidine/DMF to afford Fmoc-deprotected amino C7 CPG beads II-2. DTx-01-08 was then coupled to II-2 using HATU and DIEA in DMF to produce the fatty-acid loaded CPG beads II-3, which were subsequently treated with 3% dichloroacetic acid (DCA) in DCM to remove the DMT protecting group and afford II-4. Oligonucleotide synthesis was performed on II-4 via standard phosphoramidite chemistry. The final coupling was with a phosphoramidite (Glen Research, Catalog No.10-1906) that incorporated a monomethoxytrityl (MMTr) protected 6-carbon alkyl amine as shown in structure II-5. After removal of MMT with 3% dichloroacetic acid (DCA) in DCM, II-6 was coupled to DTx-01-08 using HATU and DIEA in DMF to yield II-7. Stepwise deprotection with triethylamine in acetonitrile (to remove phosphate protecting groups) and AMA [ammonium hydroxide (28%)/methylamine (40%) (1:1, v/v)] (to remove base protecting groups and cleave the oligonucleotide from the synthesis resin) yielded crude II-8. Purification using RP-HPLC yielded a conjugated oligonucleotide. Purity and identity of II-8 were confirmed by analytical RP-HPLC and MALDI-TOF MS using the [M+H] peak, respectively. Scheme III: Conjugation of an Uptake Motif to the 5’ Terminus of an Oligonucleotide Scheme III above illustrates the preparation of an oligonucleotide conjugated to an uptake motif at the 5’ terminus, i.e. at the 5’ carbon of the 3’ terminal nucleotide. In summary, oligonucleotide synthesis was performed on CPG beads III-1 (Glen Research, Catalog No.20-5041-xx) via standard phosphoramidite chemistry. In the last nucleotide coupling of the automated sequence, a nucleotide modified with the MMT-protected C6 linker illustrated above (Glen Research, Catalog No.10-1906) was used, yielding modified oligonucleotide-bounded CPG beads III-2. After removal of MMT with 3% dichloroacetic acid (DCA) in DCM, III-2 was coupled to DTx-01-08 using HATU and DIEA in DMF to yield III-4. Subsequent treatment with AMA [ammonium hydroxide (28%)/methylamine (40%) (1:1, v/v)] cleaved the DTx-01-08-conjugated modified oligonucleotide from the beads to generate III-5. The oligonucleotide was then purified by RP-HPLC and characterized by MALDI-TOF MS using the [M+H] peak. Duplex Formation For each of the oligonucleotides synthesized by Schemes I, II, or III and listed above, the corresponding complementary strand was prepared via standard phosphoramidite chemistry, purified by IE-HPLC, and characterized by MALDI-TOF MS using the [M+H] peak. The duplex was formed by mixing equal molar equivalents of the passenger strand (the sense strand) and guide strand (the antisense strand), heating to 90°C for 5 minutes, and then slowly cooling to room temperature. Duplex formation was confirmed by non-denaturing PAGE or non-denaturing HPLC. Example 2: Biology Experimental Methods Cell Culture. HEK293 cells were purchased from ATCC and were cultured in DMEM containing 10% Fetal Bovine Serum (FBS), 2 mM L-glutamine, 1X non-essential amino acids, 100 U/mL penicillin and 100 mg/mL streptomycin in a humidified 37°C incubator with 5% CO2. Generation of Stable Human and Mouse NRL Cell Lines.3x10^6 HEK293 cells were plated onto 10-cm tissue culture treated petri dishes in the media described herein without antibiotics. The day after plating, human or mouse NRL plasmids were transfected into HEK293 cells with Lipofectamine 2000 according to the manufacturer’s protocol. Briefly, 20 ug of each plasmid were diluted in 480 uL of DMEM without FBS or antibiotic. Separately, 50 uL of Lipofectamine 2000 was diluted in 450 uL of DMEM without FBS or antibiotic. The plasmid/DMEM and the Lipofectamine 2000/DMEM cocktails were then combined, mixed by titrating up and down and incubated for 20 minutes at room temperature to enable complex formation. The DMEM media containing FBS but lacking antibiotic (9 mL) was then added to the plasmid/Lipofectamine 2000 complexes (1 mL) and then added to cells in the 10-cm dish. The cells were incubated overnight at 37°C in the incubator. Media was then removed and replaced with DMEM containing FBS and antibiotic. Five days post-transfection, the media was replaced with DMEM containing FBS, antibiotic and 800 ug/mL geneticin to select for cells that stably express either the human or mouse NRL. The cells were cultured in this media for 30 days with media changes every 3 days. The cells were then expanded and subsequently cryopreserved. Sequencing and qPCR were utilized to confirm integration of the human or mouse NRL expression vector. Reverse Transfection of siRNA. HEK293 cells were trypsinized and diluted to 20,000 cells/well, in 90 uL of antibiotic-free media. Compounds were diluted in PBS to 100x of the desired final concentration. Separately, Lipofectamine RNAiMax (Life Technologies) was diluted 1:66.7 in media lacking supplements (e.g. FBS, antibiotic etc.). The 100x compound in PBS was then complexed with RNAiMAX by adding 1 part compound in PBS to 9 parts lipofectamine/media. Following incubation for 20 minutes, 10 uL of the compound:RNAiMAX complexes were added to a 96 well collagen coated plate. A volume of 90 ul of the cell dilution was added to each well of the 96-well plate. The plate was then placed in a humidified 37°C incubator with 5% CO2. After 24 hours, the complexes were removed and replaced with media containing antibiotics (DMEM containing 10% FBS, 2 mM L-glutamine, 1X non-essential amino acids, 100 U/mL penicillin and 100 mg/mL streptomycin). RNA was isolated 48 hours following transfection. RNA Isolation, Reverse Transcription and Quantitative PCR. RNA was isolated utilizing the RNeasy 96 kit (Qiagen) according to the manufacturer’s protocol. RNA was reverse transcribed to cDNA utilizing random primers and the high-capacity cDNA reverse transcription kit (ThermoFisher Scientific) in a SimpliAmp thermal cycler (ThermoFisher Scientific) according to the manufacturer’s instructions. Real-time quantitative PCR was performed utilizing gene-specific primers (Thermofisher Scientific; IDTDNA), TaqMan probes (Thermofisher Scientific; IDTDNA) and TaqMan fast universal PCR master mix (Thermofisher scientific) on a StepOnePlus real-time PCR system (Thermofisher Scientific) according to the manufacturer’s instructions. For analysis of quantitative PCR, mRNA expression was normalized to the expression of either 18s rRNA, β-actin or HPRT1 mRNA (housekeeping genes) utilizing the relative CT method according to the best practices proposed in Nature Protocols (Schmittgen, T.D. & Livak, K.J. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3, 1101-1108 (2008)). Intravitreal Injection. Mice were allowed to acclimatize for at least three days following their arrival from Jackson Laboratories. The day of study initiation, the mice were weighed and anesthetized with injectable anesthesia, 100 mg/kg ketamine and 5 mg/kg xylazine via intraperitoneal injection. Deep anesthesia was confirmed via toe pinch. One or both eyes were injected intravitreally under a dissecting scope with up to 1 uL of the compound of interest using a Hamilton syringe. Following injection, antibiotic (e.g. terramycin) was placed on the eye. The animal was then allowed to recover from anesthesia in the home cage on a water-recirculating heating pad. The righting reflex was confirmed prior to removing the heat pad and before returning the animal to the holding room. Target Engagement Studies in vivo in wildtype mice, humanized NRL mice and P23H mice. 3-90 days following intravitreal injection of the compound of interest or control, the mice were euthanized. The eyes were then removed, and the retinas were dissected and prepared for RNA isolation. The regions of interest were placed in RNALater immediately following dissection and stored at 4°C for 24 hours, after which the tissue was flash frozen and stored at -80°C until RNA isolation. Prior to RNA isolation and following thawing, the RNALater was removed and the tissue washed twice in PBS. Trizol was then added and RNA isolated using the RNeasy 96 kit via the manufacturer’s instructions. Target Engagement Studies In Vivo in rd10 mice. In order to prevent retinal degeneration, rd10 mice are born and reared in the dark. The intravitreal injection of compound of interest or control was performed at 30 days of age under red light conditions to prevent retinal damage. The compound of interest was dosed in the left eye and the vehicle (PBS) control in the right. The mice remained in the dark for 5 days and were then euthanized. The eyes were removed, and the retinas were dissected and prepared for RNA isolation. The regions of interest were placed in RNALater immediately following dissection.24 hours later, the tissue in RNALater was flash frozen and stored at -80°C until RNA isolation. Prior to RNA isolation and following thawing, the RNALater was removed and the tissue washed twice in PBS. Trizol was then added and RNA isolated using the RNeasy 96 kit via manufacturer’s instructions. Efficacy Studies in rd10 mice. In order to prevent retinal degeneration, rd10 mice are born and reared in the dark. The intravitreal injection of the oligonucleotide was performed as described herein at 30 days of age under red light conditions to prevent retinal damage. The compound of interest was dosed in the left eye and the vehicle (PBS) control in the right. The mice remained in the dark for 6 days and then were moved into normal light for 4 hours a day. After 9 days of 4-hour per day light exposure, the mice were moved to the dark for overnight dark adaptation. Following dark adaptation, functional assessment of the retina using electroretinography (ERG) was performed as described herein. Following euthanasia, the eyes were removed and placed in 10% neutral buffered formalin for histology. Functional Assessment of Retina using Electroretinography (ERG). Retinal function was assessed in mice following intravitreal injection of compound of interest or vehicle control (PBS). Animals were dark adapted overnight before testing. The day of study initiation, the mice were anesthetized with injectable anesthesia, 100 mg/kg ketamine and 5 mg/kg xylazine via intraperitoneal injection. Deep anesthesia was confirmed via toe pinch. ERG measurements were performed immediately with a Diagnosys Celeris rodent ERG device (Diagnosys, Lowell, MA). A mouse was placed on a heating pad at 37°C, and its pupils were moistened with 2.5% hypromellose eye lubricant (HUB Pharmaceuticals, Rancho Cucamonga, CA). Light stimulation was produced by an in-house scripted stimulation series in Espion V6 software (Diagnosys, Lowell, MA). Electroretinography was performed using a fully-integrated Celeris system (Diagnosys, Lowell, MA). For rd10 mice, scotopic (dark-adapted) ERGs were elicited at intensities of 1 cd·s/m2 (inter-stimulus interval 20s, 3 repetitions averaged), 40 cd·s/m2 (inter-stimulus interval 20s, 3 repetitions averaged). For P23H heterozygous mice, scotopic (dark-adapted) ERGs were elicited at intensities of 0.01 cd·s/m2 (inter-stimulus interval 20s, 3 repetitions averaged), 0.1 cd·s/m2 (inter-stimulus interval 20s, 3 repetitions averaged), and 1 cd·s/m2 (inter-stimulus interval 20s, 3 repetitions averaged). Eyes were then exposed to a white background light (6500 K) at 9 cd/m2 for ten minutes. Photopic (light-adapted) ERGS were elicited at intensities of 3 cd·s/m2 (ISI 2s, 3 repetitions averaged), 10 cd·s/m2 (ISI 2s, 3 repetitions averaged), and 3 cd·s/m2 flickering at 9.9 Hz (20 repetitions averaged). The ERG signal was acquired at 2 kHz and filtered with a low frequency cutoff at 0.125 Hz and a high frequency cutoff at 300 Hz. Espion software automatically detected the ERG a-waves (first negative ERG component) and b-waves (first positive ERG component). Histology. The mouse eyes were harvested and placed into 10% neutral buffered formalin (NBF) for 24 hours of fixation before standard tissue processing. Each eye was precisely sectioned to the midline where the optic nerve enters the retina. This gave consistency across all eyes within the study. Sections were dried overnight at 37oC before hematoxylin & eosin (H&E) staining was performed on the eye sections. This was achieved by dewaxing, dehydrating the sections in tap water, and immersing the sections in hematoxylin reagent for 5 mins. The sections were then washed in running tap water for two minutes before differentiation and bluing. The eosin staining was accomplished by immersing the sections into the eosin reagent for one minute before differentiations in 95% and 100% alcohols prior to placing a coverslip in xylene on the section, in preparation for microscopic examination. Target Engagement Studies in African Green Monkeys. A non-GLP study was conducted in African green monkeys at the Virscio/St. Kitts Biomedical Research Foundation facility. Healthy adult male and female animals were selected for inclusion in the study following a baseline screening to assess general and ocular health. For baseline exams and all subsequent study procedures anesthesia was achieved with intramuscular ketamine (8 mg/kg) and xylazine (1.6 mg/kg) to effect, and pupil dilation with topical 10% phenylephrine, 1% cyclopentolate and/or 1% tropicamide. Intravitreal injection was performed in both eyes on Day 0 of the study, using a 31-gauge, 0.375 inch needle inserted inferotemporally at the level of the ora serrata ~2.5 mm posterior to the limbus. Each eye was examined within 30 minutes to 1 hour of injection by slit lamp biomicroscopy following completion of each IVT injection and observations documented. A topical triple antibiotic neomycin, polymyxin, bacitracin ophthalmic ointment (or equivalent) was administered after the examination. If necessary based on examination at one (Day 1) and three days (Day 3) following IVT injection, a steroid was administered subconjunctivally. Intraocular pressure (IOP) measurements were obtained via tonometry at Day 1, Day 3, and Day 13. On Day 0, Day 1, Day 3, and Day 13, eyes were examined by slit lamp biomicroscopy to evaluate ocular health. Serum was collected via the femoral vein just prior to and four hours after IVT injection (Day 0), and on Day 1 and Day 14. Following completion of exams and serum collection on Day 14, animals were euthanized with sodium pentobarbital (100 mg/kg IV to effect). Prior to enucleation, aqueous humor (50 µL) will be sampled in both eyes with a 0.3 mL insulin syringe with a 31-gauge needle, transferred to cryotubes and stored -70oC. Eyes were sutured, enucleated and excess orbital tissue was trimmed. The iris/ciliary body of each eye was subdissected; one half was transferred to a cryotube, flash frozen and stored below -70oC and the other half was transferred to a cryotube containing 200µL of RNAlater and stored at 4 oC overnight, after which excess RNA later was removed and the sample was stored below -70oC. The remainder of the anterior segment was divided in half, with one half flash frozen for storage below -70oC and the other half transferred to a cryotube containing 200µL of RNAlater and stored at 4 oC overnight, after which excess RNAlater was removed and the sample was stored below -70oC. The vitreous was collected from the posterior eyecup with a syringe, transferred to cryotubes (2 aliquots of ~1 mL each), flash frozen then stored below -70oC. After collection of vitreous, longitudinal cuts were made in the eyecup to allow flat mounting, and the flat mount bisected in the plane intersecting the optic nerve and fovea. The flat mount was transferred to a dissection dish containing RNAlater. A 5 mm diameter punch of neural retina/RPE/choroid centered on the fovea was collected from each sample. Two 5 mm diameter punches were collected from each of the cone dense regions in the superior and inferior peripheries outside of the vascular arcade, nasal to the optic nerve, and temporal to the macula. A 3 mm diameter hemi-punch of the optic nerve head was also obtained. For all punches except the optic nerve head punch, the neural retina was separated from the RPE/choroid and each separate tissue was transferred to labeled pre-tared cryotubes containing 200µL of RNAlater, weighed and stored at 4oC overnight, after which excess RNAlater was removed, and the sample was stored below -70oC. Remaining eye tissue from the retina and choroid was placed in a cryotube and stored below -70oC. Example 3: Identification and activity of siRNAs targeting mouse NRL Several siRNAs targeting mouse NRL were designed and are shown in Table A. Compounds DT-000126 to DT-000133 are targeted to mouse NRL. Compound DT-000112 is targeted to both mouse and human NRL. The sense and antisense strands of the compounds in Table A were prepared with sugar moiety and internucleotide linkage modifications to increase hybridization affinity, minimize degradation by nucleases, and enhance loading into RISC. From the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoronucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides; nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the final two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; all other internucleotide are phosphodiester internucleotide linkages. A hydroxyl group is present at the 5’ carbon of the 3’ terminal nucleotide and the 3’ carbon of the 3’ terminal nucleotide. From the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methylnucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides; nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the final two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; all other internucleotide are phosphodiester internucleotide linkages. A phosphate group is present at the terminal 5’ carbon and a hydroxyl group is present at the 3’ carbon of the 3’ terminal nucleotide. Table A: siRNAs Targeting mouse NRL HEK cells were engineered to express mouse neural retina leucine zipper (NRL) for the purpose of identifying siRNAs that inhibit the expression of NRL and are suitable for in vivo characterization. The HEK-NRL cells were than transfected with siRNAs at doses ranging from 3 to 100 nM. RNA was then isolated 48 hours later, reverse transcribed to cDNA and NRL expression was quantified by qPCR. The average NRL expression for each of four replicates was calculated and shown in Table B. Several of the siRNAs targeted to mouse NRL inhibited NRL expression in a dose-dependent manner. Table B: Screen of Mouse siRNAs in HEK Cells Expressing Mouse NRL Example 4: In Vivo Activity of siRNAs targeting mouse NRL in wild-type mice To evaluate the in vivo activity of compounds targeting NRL, the 3’ terminus of the sense strand of certain compounds was conjugated to a long chain fatty acid (LCFA) domain or “uptake motif” which improves the uptake of nucleic acid compounds into cells (International Patent Application Publication No. WO 2019/232255). Conjugated compounds were formed as in the structures below, where the nucleotide shown is the 3’ terminal nucleotide, “B” is nucleobase and “R” is the substituent at the 2’ carbon of the nucleoside sugar. The uptake motif DTx-01-08 was conjugated to the sense strand, using the “C7OH” linker attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand via the phosphate group to form the conjugate group named “C7OH- [DTx-01-08]. The uptake motif DTx-01-32 was conjugated to the sense strand, using the “C7OH” linker attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand via the phosphate group to form the conjugate group named “C7OH- [DTx-01-32]. The conjugated compounds are shown in Table C. Nucleotide modifications are as indicated above. Table C: LCFA-Conjugated siRNAs targeting mouse NRL Compounds conjugated to DTx-01-08 were tested for their ability to inhibit the expression of NRL in the eye of wild-type mice.10 ug of each of DT-000239 to DT-000243 was injected via intravitreal injection into each eye of wildtype mice. Seven days following injection, retinas were collected, RNA isolated, reverse transcribed to cDNA and NRL expression quantified by qPCR. The average percent NRL expression from 8 eyes was calculated and is shown in Table D. Table D: In Vivo Activity of Conjugated mouse NRL siRNA DT-000239 suppressed NRL expression to the greatest degree and thus, was further evaluated in in vivo dose-response studies. To compare different LCFA motifs, also tested was DT-000244, which has the same sense strand and antisense strand as DT-00239, but the sense strand is conjugated to DTx-01-32 rather than DTx-01-08. Compounds DT-000239 and DT-000244 were tested for their ability to reduce the expression of NRL in wild-type mice. C57BL/6J mice at five to six weeks of age received an intravitreal (IVT) injection of 1 ug, 3 ug, or 10 ug of DT-000239 or DT-000244. Vehicle (PBS) and a conjugated siRNA targeting PTEN (DT-000137) were used as control treatments. Seven days following IVT injection, the mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The level of mouse NRL mRNA was measured by quantitative real-time PCR. The average percentage expression from 8 eyes (compound treatment) or 16 eyes (PBS treatment) was calculated and is shown in Table E. The data illustrate that both DT-000239 and DT-000244 reduced NRL expression in the retina following IVT injection. The inhibitory activity of DT-000239 was slightly greater than that of DT-000244, thus DT-000239 was selected for further in vivo testing. Table E: Silencing of NRL Following IVT Injection of Conjugated siRNAs To determine the duration of action of DT-00239, a time-course experiment was performed. C57BL/6J mice at five to six weeks of age received an intravitreal (IVT) injection of 10 ug of DT-000239. Vehicle (PBS) was used as a control treatment. At three, seven, 14 and 28 days following the injection, the mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The level of mouse NRL mRNA was measured by quantitative real-time PCR. The average percentage expression from eight eyes for each treatment at each timepoint was calculated and is shown in Table F. A single injection of DT-000239 resulted in repressed NRL expression out to 28 days. As NRL levels were not yet increasing at 28 days, the duration of action is at least 28 days. Table F: Duration of Action Following IVT Injection of Conjugated siRNAs As the suppression of NRL also alters the expression of a subset of rod and cone genes, certain rod and cone genes were also selected for measurement of mRNA levels in juvenile mice. C57BL/6J mice at 14 days of age received an IVT injection of 10 ug of DT-000239 in the right eye, and PBS in the left eye. The PTEN-targeting siRNA DT-000137 was used as a control compound, with DT-000137 injected in the right eye and PBS injected in the left eye. At 14 days after injection, the mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The level of PTEN, NRL, NR2E3, GNB3, REEP6, AAR3, and GNAT1 mRNA was measured by quantitative real-time PCR. The average percentage expression from nine replicates for each treatment was calculated and is shown in Table G. Consistent with literature reports, the inhibition of NRL also resulted in decreases in the expression of the rod genes REEP6, NR2E3, and GNAT1, and increases in the expression of the cone genes ARR3 and GNB3. Table G: Alteration in Gene Expression 14 Days Following a Single IVT Injection of siRNA in Juvenile Wild-Type Mice A similar experiment was performed in older mice. C57BL/6J mice at 35 days of age received an IVT injection of 10 ug of DT-000239 in the right eye, and PBS in the left eye. At 42 days of age and 14 days after injection, the mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The level of NRL, NR2E3, GNB3, REEP6, ARR3, and GNAT1 mRNA was measured by quantitative real-time PCR. The average percentage expression from eight eyes for each treatment was calculated and is shown in Table H. Similar to the observation in juvenile mice, inhibition of NRL also resulted in decreases in the expression of the rod genes REEP6, NR2E3, and GNAT1, and increases in the expression of the cone genes ARR3 and GNB3. Table H: Alteration in Gene Expression 14 Days Following a Single IVT Injection of siRNA in Adult Wild-Type Mice Example 5: Evaluation of siRNAs targeting NRL in the rd10 mouse model of retinal degeneration An accepted experimental model of retinitis pigmentosa (RP) is the rd10 mouse model of retinal degeneration, which carries a homozygous phosphodiesterase 6-beta missense mutation on a C57BL/6 J background. rd10 mice exhibit progressive retinal outer nuclear layer degeneration beginning at 16 days, sclerotic retinal vessels at four weeks of age, and a progressive decline in rod and cone electroretinogram a- and b- waves. Raising rd10 mice in total darkness has been reported to delay retinal degeneration (Chang et al., 2007, Vision Res., 47(5): 624–633). The effects of inhibiting NRL were evaluated in rd10 mice. In order to prevent retinal degeneration, rd10 mice were born and reared in the dark. At 27 days of age, 10 ug of DT-000239 was injected into the right eye and PBS was injected into the left eye. The mice remained in the dark until 31 days of age, at which time the mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The level of NRL was measured by quantitative real-time PCR. The average percentage expression from seven eyes for each treatment was calculated. Following injection of DT-000239, the mean NRL mRNA level was 21.97% (SEM 9.9). Following injection of PBS, the mean NRL mRNA level was 120.6% (SEM 18.55). The effects of DT-000239 on photoreceptor function in rd10 mice were assessed by ERG. In order to prevent retinal degeneration, rd10 mice were born and reared in the dark. At 27 days of age, 10 ug of DT-000239 was injected into the right eye and PBS (vehicle) was injected into the left eye. At day 33, the mice were exposed to normal light for four hours per day, for each of the following 11 days. After 11 days of 4-hour light exposure (i.e., at day 44), the mice were moved to the dark for overnight dark adaptation. Following dark adaptation, functional assessment of the retina using electroretinography (ERG) was performed. Following euthanasia, the eyes were removed and processed for histological analysis. Hematoxylin & eosin staining was used to visualize photoreceptor cells. ERG results are shown in Table I. Scotopic wave measurements that target rod-pathway function are made from the dark-adapted eye, whereas photopic wave measurement that target cone-pathway function are made from the light-adapted eye. The data illustrate that inhibition of NRL protected photoreceptor function. Histological analysis of retina sections revealed a dramatic preservation of the photoreceptor layer following inhibition of NRL. Representative images of H&E staining of DT-000239 and PBS-treated retinas from an individual animal are shown in FIG.1A and 1B. Table I: Preservation of Photoreceptor Function Following Inhibition of NRL in rd10 mice Example 6: Evaluation of siRNAs targeting NRL in the P23H mouse model of retinitis pigmentosa Compounds provided herein were tested in an experimental mouse model of heterozygous P23H retinitis pigmentosa (P23H RP mice). P23H RP mice carry a point mutation in the rhodopsin gene sequence, whereby a cytosine is substituted with adenine, resulting in the normal “CCC” codon encoding proline being replaced with the “CAC” codon encoding histidine. The phenotype of P23H mice recapitulates the retinopathy and progressive retinal degeneration observed in humans with autosomal dominant retinitis pigmentosa caused by the P23H mutation. The P23H RP model was used to study the effects of targeting NRL. As the suppression of NRL also alters the expression of a subset of rod and cone genes, certain rod and cone genes were also selected for measurement of mRNA levels. P23H RP mice at 14 days of age received a single IVT injection of 10 ug of DT-000239 in the right eye, and PBS (vehicle) in the left eye. A control group of P23H RP mice at 14 days of age received an injection of 10 ug of DT-000137 which targets PTEN. At 14 days post-injection, the mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The levels of NRL, PTEN, the rod genes NR2E3, REEP6 and GNAT1 and cone genes GNB3 and ARR3 were measured by quantitative real-time PCR. The average percentage expression from eight or nine for each treatment was calculated and is shown in Table J. Consistent with literature reports, the inhibition of NRL also resulted in decreases in the expression of the rod genes REEP6, NR2E3, and GNAT1, and increases in the expression of the cone genes ARR3 and GNB3. Table J: Alteration in Gene Expression 14 days Following a Single IVT Injection of Conjugated siRNA in 15-Day-Old P23H Mice An additional study in P23H RP mice was performed to evaluate the effect of NRL inhibition on photoreceptor function and preservation. At 28, 61, and 111 day of age, P23H RP mice received a 10 ug IVT injection of DT-000239 in the right eye and PBS (vehicle) in the left eye. Retinal function was measured using electroretinography (ERG) at multiple timepoints. Following euthanasia at day 139, the eyes were removed and processed for histological analysis. Hematoxylin & eosin staining was used to visualize photoreceptor cells. Mean ERG results at each time point are shown in Table K and FIG.2A and 2B. Scotopic wave measurements that target rod-pathway function are made from the dark-adapted eye, whereas photopic wave measurement that target cone-pathway function are made from the light-adapted eye. The data illustrate that inhibition of NRL protected photoreceptor function. Table K: Preservation of Photoreceptor Function Following Inhibition of NRL in P23H Retinitis Pigmentosa Mice
Histological analysis of retina sections revealed preservation of the photoreceptor layer following inhibition of NRL. Representative images of H&E staining of DT-000239 and PBS-treated retinas from an individual animal are shown in FIG.3A and 3B. Example 7: Design and Testing of siRNAs Targeting Mouse and Human NRL To allow for testing of human-targeted siRNAs in mouse experimental models, siRNAs were designed to have an antisense strand that is fully complementary to both the human and mouse NRL mRNAs, i.e. siRNAs that are fully human/mouse cross-reactive. The siRNAs are shown in Table L. In Table L, “Start” and “End” correspond to the 5’ and 3’ nucleotide positions of the 19-nucleotide sequence of the human NRL mRNA (NCBI Reference Sequence NM_006177.5, deposited with GenBank on June 2, 2019; SEQ ID NO: 1) to which nucleotides 1 to 19 of the sense strand are identical, and the 5’ and 3’ nucleotide positions of the 19-nucleotide sequence of the human NRL mRNA to which nucleotides 1 to 19 of the antisense strand are complementary. Each row represents a sense and antisense strand pair of an siRNA. Each antisense strand is 21 nucleotides in length and has the modified nucleotide pattern according to Formula I. From the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methylnucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides; nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the final two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; all other internucleotide are phosphodiester internucleotide linkages. A phosphate group is present at the 5’ carbon of the 3’ terminal nucleotide and a hydroxyl group is present at the 3’ carbon of the 3’ terminal nucleotide. Each sense strand is 21 nucleotides in length and has the modified nucleotide pattern according to Formula II. From the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoronucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides; nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the final two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; all other internucleotide are phosphodiester internucleotide linkages. A hydroxyl group is present at the 5’ carbon of the 3’ terminal nucleotide and the 3’ carbon of the 3’ terminal nucleotide. Modified sugar moieties are indicated by a subscript notation following the nucleotide, and modified internucleotide linkages are indicated by a superscript notation. A nucleotide followed by the subscript “F” is a 2’-fluoro nucleotide; a nucleotide followed by the subscript “M” is a 2’-O-methyl nucleotide; and a nucleotide without a subscript is a beta-D-deoxyribonucleotide. A superscript “S” is a phosphorothioate internucleotide linkage; all other internucleotide linkages are phosphodiester internucleotide linkages. For example “UFSCM” is a 2’-fluorouridine linked to a 2’-O-methylcytidine by a phosphorothioate internucleotide linkage. “GMUF” is a 2-O-methylguanosine linked to a 2’-fluorouridine by a phosphodiester internucleotide linkage.
Table L: Fully Human/Mouse Cross-Reactive siRNAs Targeting NRL MGFGMUFGMGF AFAMGFGMAFGM T 21MAFCMAFUMCFGFCMCFAMGFCMG 23MUFGMGFGMUFGFGMAFGMGFCM T 31 HEK cells engineered to express human NRL were transfected as described herein across a series of separate experiments. Cells were transfected with 10 nM or 1 nM of each siRNA. Following a 48-hour incubation period, cells were harvested, RNA was isolated, and the level of NRL mRNA was measured by quantitative real-time PCR and reported relative to the level of NRL mRNA in PBS treated cells. The average percentage expression for PBS treatment was calculated from 4 to 16 replicates. The average percentage expression for each siRNA treatment was calculated from four replicates. The data are shown in Table M. Table M: In vitro Activity of Fully Human/Mouse Cross-Reactive siRNAs Targeting NRL To evaluate the in vivo activity of fully human/mouse cross-reactive compounds targeting NRL, the 3’ terminus of the sense strand of certain compounds was conjugated to a long chain fatty acid (LCFA) domain or “uptake motif” which improves the uptake of nucleic acid compounds into cells (International Patent Application Publication No. WO 2019/232255). Conjugated compounds were formed as in the structure below, where the nucleotide shown is the 3’ terminal nucleotide, “B” is nucleobase and “R” is the substituent at the 2’ carbon of the nucleoside sugar. The uptake motif DTx-01-08 was conjugated to the sense strand, using the “C7OH” linker attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand via the phosphate group to form the conjugate group named “C7OH- [DTx-01-08]. The compounds are shown in Table N.
Table N: Conjugated fully human/mouse cross reactive siRNAs targeting NRL Compounds conjugated to DTx-01-08 were tested for their ability to inhibit the expression of NRL in the eye of wild-type mice.10 ug of each compound was injected via intravitreal injection into each eye of wildtype mice at 35 days of age. Vehicle (PBS) and a conjugated siRNA targeting PTEN (DT-000137) were used as control treatments. Seven days following injection, retinas were collected, RNA isolated, reverse transcribed to cDNA and NRL expression quantified by qPCR. The average percent NRL expression from 8 eyes was calculated and is shown in Table O. Table O: In Vivo Activity of Conjugated Fully Human/Mouse Cross-Reactive siRNAs While inhibition of NRL mRNA was observed, the inhibitory activity of the fully human/mouse cross-reactive siRNAs was not robust enough for further development of these siRNAs as candidate therapeutic agents. Example 8: Design and Testing of siRNAs Targeting Human NRL As the library of human/mouse NRL cross-reactive siRNAs did not identify suitable candidates for further development as therapeutic agents, additional siRNAs were designed to be fully complementary to the human NRL mRNA, with a focus on regions of homology between human and mouse NRL mRNAs. These siRNAs were designed with the goal of identifying siRNAs that are suitably potent and efficacious against human NRL while also sufficiently activity against mouse NRL to enable testing in experimental mouse models. The siRNAs are shown in Table P. In Table P, “Start” and “End” correspond to the 5’ and 3’ nucleotide positions of the 19-nucleotide sequence of the human NRL mRNA (NCBI Accession No. NM_006177.5) to which nucleotides 1 to 19 of the sense strand are identical, and the 5’ and 3’ nucleotide positions of the 19-nucleotide sequence of the human NRL mRNA to which nucleotides 1 to 19 of the antisense strand are complementary. Each row represents a sense and antisense strand pair of an siRNA. Each antisense strand is 21 nucleotides in length and has the modified nucleotide pattern according to Formula I. From the 5’ terminus of the antisense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-O-methylnucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-fluoro nucleotides; nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the final two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; all other internucleotide are phosphodiester internucleotide linkages. A phosphate group is present at the 5’ carbon of the 3’ terminal nucleotide and a hydroxyl group is present at the 3’ carbon of the 3’ terminal nucleotide. Each sense strand is 21 nucleotides in length and has the modified nucleotide pattern according to Formula II. From the 5’ terminus of the sense strand, nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2’-fluoronucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2’-O-methyl nucleotides; nucleotides 20 and 21 are beta-D-deoxythymidine nucleotides; the first two internucleotide linkages at the 5’ terminus and the final two internucleotide linkages at the 3’ terminus are phosphorothioate internucleotide linkages; all other internucleotide are phosphodiester internucleotide linkages. A hydroxyl group is present at the 5’ carbon of the 3’ terminal nucleotide and the 3’ carbon of the 3’ terminal nucleotide. Nucleotide modifications are indicated for each sense strand and antisense strand. Modified sugar moieties are indicated by a subscript notation following the nucleotide, and modified internucleotide linkages are indicated by a superscript notation. A nucleotide followed by the subscript “F” is a 2’-fluoro nucleotide; a nucleotide followed by the subscript “M” is a 2’-O-methyl nucleotide; and a nucleotide without a subscript is a beta-D-deoxyribonucleotide. A superscript “S” is a phosphorothioate internucleotide linkage; all other internucleotide linkages are phosphodiester internucleotide linkages. For example, “UFSCM” is a 2’-fluorouridine linked to a 2’-O-methylcytidine by a phosphorothioate internucleotide linkage. “GMUF” is a 2-O-methylguanosine linked to a 2’-fluorouridine by a phosphodiester internucleotide linkage. HEK cells engineered to express human NRL were transfected as described herein across a series of separate experiments (i.e., separate experiments conducted in different multi-well plates). Cells were transfected with 10 nM or 1 nM of each siRNA. Following a 48-hour incubation period, cells were harvested, RNA was isolated, and the level of NRL mRNA was measured by quantitative real-time PCR and reported relative to the level of NRL mRNA in PBS treated cells from the same experiment (i.e., the PBS control from the same multi-well plate). The average percentage expression for PBS treatment was calculated from 4 to 16 replicates. The average percentage expression for each siRNA treatment was calculated from four replicates. The data are shown in Table Q. Table Q: In Vitro Activity of siRNAs Targeted to NRL
The in vitro screening data revealed siRNAs that were active within regions of the NRL coding region. The boundaries of active regions were selected based on the 5’ and 3’ target sites of siRNAs with at least 50% inhibitory activity. Additional target sites were included even if the siRNA resulted in less than 50% inhibitory activity but overlapped with the target region of one or more active siRNAs. These regions are listed in Table R. Table R: siRNA-Active Regions of human NRL coding region Example 9: In Vivo Testing of Human NRL siRNAs Human NRL siRNAs that were active within certain target regions of the NRL mRNA were selected for conjugation to uptake motifs and testing in wild-type mice and the rd10 model of retinitis pigmentosa. Due to the homology between the human and mouse NRL mRNAs, certain siRNAs designed to be perfectly complementary to the human NRL mRNA will have sufficient complementarity to the mouse NRL mRNA to inhibit expression of mouse NRL. Conjugated compounds were formed as in the structures below, where the nucleotide shown is the 3’ terminal nucleotide, “B” is nucleobase and “R” is the substituent at the 2’ carbon of the nucleoside sugar. The uptake motif DTx-01-08 was conjugated to the sense strand, using the “C7OH” linker attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand via the phosphate group to form the conjugate group named “C7OH- [DTx-01-08]. The uptake motif DTx-01-32 was conjugated to the sense strand, using the “C7OH” linker attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand via the phosphate group to form the conjugate group named “C7OH- [DTx-01-32]. The conjugated compounds are shown in Table S. Each conjugated sense strand is 19 nucleotides in length and does not have the 3’ terminal beta-D-deoxythymidine nucleotides present in the corresponding unconjugated sense strand. Nucleotide modifications are indicated as described herein. Table S: Conjugated human NRL siRNAS Target Engagement in Wild-Type Mice Compounds DT-000429, DT-000430, DT-000431, and DT-000432 were tested for their ability to reduce the expression of NRL in wild-type mice. The mouse compound DT-000239 was also tested in this experiment. Vehicle (PBS) was used as a control treatment. C57BL/6J mice at five to six weeks of age received a single intravitreal (IVT) injection of 10 ug of compound, or a single IVT injection of PBS. Seven days following IVT injection, the mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The level of mouse NRL mRNA was measured by quantitative real-time PCR. The average percentage expression from 8 eyes was calculated and is shown in Table T. The data illustrate that DT-000239, described above, and each of DT-00429, DT-000430, DT-000431 and DT-000432 reduced NRL expression in the retina seven days following IVT injection. Table T: Silencing of NRL Following IVT Injection of Conjugated human NRL siRNAs A time-course experiment was conducted to compare the duration of action of DT-00239, DT-000429, DT-000430, and DT-000432. C57BL/6J mice at five to six weeks of age received an intravitreal (IVT) injection of 10 ug of DT-000239, DT-000429, DT-000430, or DT-000432. Vehicle (PBS) was used as a control treatment. At seven, 14, 28, 60, and 90 days following the injection, mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The level of NRL mRNA remaining was measured by quantitative real-time PCR. The average percentage expression from eight eyes for each compound treatment and seven to eight eyes for PBS treatment at each timepoint was calculated and is shown in Table U. Table U: Duration of Action Following IVT Injection of Conjugated NRL siRNAs To further assess the duration of action of DT-000239, DT-000430, and DT-000432, an additional time-course experiment was performed. C57BL/6J mice at five to six weeks of age received an intravitreal (IVT) injection of 10 ug of DT-000239, DT-000430, or DT-000432. Vehicle (PBS) was used as a control treatment. At three, 14, 28, 60, and 90 days following the injection, mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The level of mouse NRL mRNA was measured by quantitative real-time PCR. Also measured by real-time PCR were the levels of NR2E3, GNB3, REEP6, AAR3, and GNAT1 mRNA. The average percent NRL mRNA level from eight eyes for each treatment at each timepoint was calculated and is shown in Table V. “ND” indicates that data was not collected for a particular time point. The average percent NRL mRNA suppression over time is shown in FIG.4. As evidenced by NRL suppression, both DT-000430 and DT-000432 resulted in a long duration of effect in the mouse retina, with the effect of DT-000432 being slightly greater in this experiment. The inhibition of NRL was accompanied by decreases in the expression of the rod genes REEP6, NR2E3, and GNAT1, and increases in the expression of the cone genes ARR3 and GNB3, particularly in the first 28 days after the injection of compound. Table V: Duration of Action Following IVT Injection of Conjugated NRL siRNAs
Activity in the rd10 Model of Retinitis Pigmentosa An accepted experimental model of retinitis pigmentosa (RP) is the rd10 mouse model of retinal degeneration, which carries a homozygous phosphodiesterase 6-beta missense mutation on a C57BL/6 J background. rd10 mice exhibit progressive retinal outer nuclear layer degeneration beginning at 16 days, sclerotic retinal vessels at four weeks of age, and a progressive decline in rod and cone electroretinogram a- and b- waves. Raising rd10 mice in total darkness has previously been reported to delay retinal degeneration. The effects of human NRL siRNAs were evaluated in rd10 mice. In order to prevent retinal degeneration, rd10 mice were born and reared in the dark. At 31 days of age, mice received IVT injections of 1ug, 3ug, or 10 ug of DT-000430 was injected into the left eye, and PBS was injected into the right eye. After five days, mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The level of NRL was measured by quantitative real-time PCR. Also measured was the expression of the rod genes REEP6, NR2E3, and GNAT1, and the cone genes ARR3 and GNB3. The average percentage expression for each treatment in the DT-000430 experiment (n = 16 for PBS; n = 6 for DT-000430) was calculated and is shown in Table W. The average percentage expression for each treatment in the DT-000432 experiment (n = 15 for PBS; n = 5 for DT-000430) was calculated and is shown in Table X. Each compound resulted in the dose-dependent suppression of NRL and NRL target genes NR2E3, REEP6, and GNAT1. The expression of the cone gene GNB3 increased in a dose-dependent manner, while the expression of the cone gene ARR3 was not significantly altered. Table W: Dose-Dependent Suppression of Genes by Conjugated Human NRL siRNA in rd10 Mice Table X: Dose-Dependent Suppression of Genes by Conjugated Human NRL siRNA in rd10 Mice The effects of DT-000430 and DT-000432 on photoreceptor function in rd10 mice were assessed by ERG. In order to prevent retinal degeneration, rd10 mice were born and reared in the dark. At 30 days of age, 10 ug of compound was injected into the left eye and PBS was injected into the right eye.14 days later, mice were exposed to light for four hours per day for each of the following nine days. After the nine days of light exposure, the mice were moved to the dark for overnight dark adaptation. Following dark adaptation, functional assessment of the retina using electroretinography (ERG) was performed. Following euthanasia, the eyes were removed and processed for histological analysis. Hematoxylin & eosin staining was used to visualize photoreceptor cells. ERG results are shown in Table Y. Scotopic wave measurements that target rod-pathway function are made from the dark-adapted eye, whereas photopic wave measurement that target cone-pathway function are made from the light-adapted eye. The data illustrate that inhibition of NRL protected photoreceptor function. Table Y: Preservation of Photoreceptor Function Following Inhibition of NRL in rd10 mice Histological analysis of retina sections from a separate but similarly designed study with DT-000430 and DT-000432 revealed a dramatic preservation of the photoreceptor layer following inhibition of NRL. Representative images of H&E staining of PBS-treated and DT-000430-treated retinas from an individual animal are shown in FIG.5A and 5B. Representative images from PBS-treated and DT-000432-treated retinas from an individual animal are shown in FIG.5C and 5D. In another separate but similarly designed study with DT-000430, H&E staining was performed on retina fixed in Davidson’s fixative—an approach that more optimally preserves retinal structures relative to formalin fixation. Representative PBS-treated and DT-000430-treated retinas from an individual animal are shown in FIG.6A and 6B. Based on the studies in wild-type and rd10 mice, DT-000430 and DT-000432 were identified as suitable compounds for further optimization. Although the nucleotide sequences of DT-000430 and DT-000432 each contain a mismatch to the mouse NRL mRNA, the data illustrated that the mismatches were tolerated well enough for the compounds to be evaluated in experimental mouse models. Example 10: Optimization of NRL siRNAs To determine whether variations in siRNA nucleotide sequence and/or modified nucleotide pattern would yield compounds with improved properties such as potency and duration of action, further compounds targeting NRL were designed and tested. These compounds are shown in Tables Z and AA. DT-000726, DT-000727, and DT-000734 (Table Z) are derived from DT-000430 and vary in the length of each strand and chemical modifications. DT-000776, DT-000777, and DT-000778 (Table AA) are conjugated versions of DT-000726, DT-000727, and DT-000734, respectively. DT-000782, DT-000783, and DT-000784 (Table Z) are derived from DT-000432 and vary in the length of each strand and chemical modifications. DT-000785, DT-000786, and DT-000787 (Table AA) are conjugated versions of DT-000782, DT-000783, and DT-000784, respectively. Compounds DT-000735, DT-000736, DT-000737, DT-000738, DT-000828, DT-000829, DT-000830, DT-000831, and DT-000832 (Table Z) are conjugated versions of siRNAs shown in Table P. Nucleotide modifications, uptake motifs and linkers are indicated as described herein. In Table AA, the uptake motif DTx-01-32 was conjugated to the sense strand, using the “C7OH” linker attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand via the phosphate group to form the conjugate group named “C7OH-[DTx-01-32]. Tbl AA Addii l C j d H NRL iRNA
Example 11: Comparison of siRNA Designs in wild-type mice Compounds DT-000776, DT-000777, and DT-000778 (chemical modification and length variants of DT-000430) were tested for their ability to reduce the expression of NRL in wild-type mice, and compared to the activity of compounds DT-000430 and DT-000432. Vehicle (PBS) was used as a control treatment. For a seven-day study, C57Bl/6J mice at five to six weeks of age received a single intravitreal (IVT) injection of 3 ug or 10 ug of compound, or a single IVT injection of PBS, in each eye. Seven days following the IVT injection, mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. For a 28 day-study, C57Bl/6J mice at five to six weeks of age received a single IVT injection of 10 ug of compound or PBS in each eye. At 28 days following the IVT injection, mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The level of mouse NRL mRNA was measured by quantitative real-time PCR. The average percentage expression from eight eyes (four mice per treatment) was calculated and is shown in Tables BB (7 days) and CC (28 days). In this experiment, comparison of the average NRL mRNA remaining at the 3 ug dose demonstrated a greater potency for DT-000776 than its parent compound DT-000430. Additionally, based on the 28-day data, DT-000776 and DT-000778 appeared to have a longer duration of action. Table BB: Silencing of NRL Seven Days Following IVT Injection of Conjugated Human NRL siRNAs Table CC: Silencing of NRL 28 Days Following IVT Injection of Conjugated Human NRL siRNAs Compounds DT-000785, DT-000786, and DT-000787 (chemical modification and length variants of DT-000432) were tested for their ability to reduce the expression of NRL in wild-type mice and compared to the activity of compounds DT-000430 and DT-000432. Vehicle (PBS) was used as a control treatment. For a seven-day study, C57Bl/6J mice at five to six weeks of age received a single intravitreal (IVT) injection of 3 ug or 10 ug of compound, or a single IVT injection of PBS, in each eye. Seven days following the IVT injection, mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. For a 28 day-study, C57Bl/6J mice at five to six weeks of age received a single IVT injection of 10 ug of compound or PBS in each eye. At 28 days following the IVT injection, mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The level of mouse NRL mRNA was measured by quantitative real-time PCR. The average percentage expression from eight eyes (four mice per treatment) was calculated and is shown in Tables DD (7 days) and EE (28 days). In this experiment, DT-000432 appeared more potent than DT-000785, DT-000786, and DT-000787. Comparison of the 10 ug dose data at 7 days and 28 days reveals a similar duration of action for DT-00432 and its derivative compounds DT-000785, DT-000786, and DT-000787. Table DD: Silencing of NRL Seven Days Following IVT Injection of Conjugated Human NRL siRNAs Table EE: Silencing of NRL 28 Days Following IVT Injection of Conjugated Human NRL siRNAs Compounds DT-000735 and DT-000736 target regions of NRL that overlap with the target region of DT-000430. Compounds DT-000737 and DT-000738 target regions of the NRL mRNA that overlap with the target region of DT-000432. These compounds were tested for their ability to reduce the expression of NRL in wild-type mice and compared to the activity of compounds DT-000430 and DT-000432. Vehicle (PBS) was used as a control treatment. C57BL/6J mice at five to six weeks of age received a single intravitreal (IVT) injection of 10 ug of compound, or a single IVT injection of PBS, in each eye. At seven and 28 days following IVT injection, mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The level of mouse NRL mRNA was measured by quantitative real-time PCR. The average percentage expression from eight eyes (four mice per treatment) was calculated and is shown in Table FF. These data illustrate that DT-000432 is more efficacious than DT-000737 and DT-000738 and has a longer duration of action than DT-000737. The efficacy and duration of action of DT-000735 and DT-000736 are similar to that of DT-000430. Table FF: Silencing of NRL Following IVT Injection of Conjugated Human NRL siRNAs Example 12: Evaluation of NRL siRNA Compounds in Humanized NRL Mice Due to differences between human and mouse NRL mRNA nucleotide sequence, siRNA compounds with an antisense strand that is fully complementary to the human NRL mRNA may have one or more nucleotides that are not complementary to the mouse NRL mRNA. To enable the evaluation of human-specific NRL siRNAs in experimental mouse models, wild-type mice were genetically modified to replace one endogenous mouse NRL allele with a human NRL sequence, so that the mice express one mouse NRL mRNA and one human NRL mRNA. The genetic engineering was performed by the Genetic Engineering Technologies group at The Jackson Laboratory. Briefly, the CRISPR/Cas9 genome editing technology was employed to excise the mouse genomic Nrl (from codon 2 to the stop codon) and insert the human genomic NRL (from codon 2 to the stop codon) at the mouse Nrl start codon. This resulted in the generation of founder mice, on a C57Bl/6J background, which were bred to wild-type C57Bl/6J mice to produce an “N1” generation. The NRL genes of animals from the N1 generation were analyzed by gene sequencing to identify individual animals with one mouse NRL allele and one correctly inserted human NRL allele, or “humanized NRL mice.” These animals were then used to evaluate the activity of NRL-targeting siRNA compounds. Compounds DT-000430, DT-000432, and DT-000776 are cross-reactive with both mouse and human NRL mRNA. Compounds DT-000828, DT-000829, DT-000830, DT-000831, and DT-000832 are specific to the human NRL mRNA. Each of these compounds was tested in the humanized NRL mouse model. Vehicle (PBS) was used as a control treatment. Humanized NRL mice at five to six weeks of age received a single intravitreal (IVT) injection of 3 ug or 10 ug of compound, or a single IVT injection of PBS, in each eye. At seven days following IVT injection, mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The levels of both mouse and human NRL mRNAs was measured by quantitative real-time PCR. The average percentage expression from eight eyes (four mice per treatment) was calculated and is shown in Table GG. As shown in Table GG and Figure 7, each compound tested was more efficacious in reducing the human NRL mRNA (Figure 7A) than the mouse NRL mRNA (Figure 7B). Of all the compounds tested, DT-000776 was surprisingly potent and efficacious in reducing the level of the human NRL mRNA, given that each compound is fully complementary to the human NRL mRNA. siRNAs with multiple mismatches the mouse NRL mRNA exhibited little or no ability to reduce NRL expression. Table GG: Reduction of NRL mRNA in Humanized NRL Mice Following IVT Injection of Conjugated Human NRL siRNAs
Compounds DT-001373, DT-001374, and DT-001375 are specific to the human NRL mRNA. The duration of action of each of these compounds was tested in the humanized NRL mouse model described herein. Vehicle (PBS) was used as a control treatment, and DT- 000776 was used as a comparator treatment. Groups of humanized NRL mice at five to six weeks of age received a single intravitreal (IVT) injection of 10 ug of compound, or a single IVT injection of PBS, in each eye. At 30 days, 60 days, 90 days and 189 days following IVT injection, groups of mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The level of human NRL mRNA was measured by quantitative real-time PCR. The average percentage expression from eight eyes (four mice per treatment) was calculated and is shown in Table HH. As shown in Table HH, each compound tested was efficacious in reducing the human NRL mRNA. Table HH: Reduction of NRL mRNA in Humanized NRL Mice Following IVT Injection of Conjugated Human NRL siRNAs Compound DT-001386 is specific to the human NRL mRNA and was tested in the humanized NRL mouse model described herein. Vehicle (PBS) was used as a control treatment, and DT-000776 was used as a comparator treatment. Groups of humanized NRL mice at five to six weeks of age received a single intravitreal (IVT) injection of 0.3 ug compound, 1 ug compound, or 3 ug of compound, or a single IVT injection of PBS, in each eye. At seven days following IVT injection, mice were euthanized, the eyes were removed, and the retinas were dissected and prepared for RNA isolation. The level of human NRL mRNA was measured by quantitative real-time PCR. The average percentage expression from eight eyes (four mice per treatment) was calculated and is shown in Table II. Both compounds were efficacious in reducing the human NRL mRNA in a dose-responsive manner. Table II: Silencing of NRL in Humanized NRL Mice Following IVT Injection of Conjugated Human NRL siRNAs Example 13: Further In Vivo Testing of Human NRL siRNAs in the rd10 mouse model Compounds DT-000430 and DT-000776 were evaluated for therapeutic benefit in rd10 mice. In order to prevent retinal degeneration, rd10 mice were born and reared in the dark. At 32 days of age, 10 ug of DT-000430, 3 ug of DT-000776, or 10 ug of DT-000776 was injected into the left eye and PBS was injected into the right eye (n = 7 mice for DT-000430; n = 8 for DT-000776).5 days later, mice were exposed to light for four hours per day for each of the following 10 days. After the nine days of light exposure, the mice were moved to the dark for overnight dark adaptation. Following dark adaptation, functional assessment of the retina using electroretinography (ERG) was performed. Following euthanasia, the eyes were removed and processed for histological analysis. Hematoxylin & eosin staining was used to visualize photoreceptor cells. ERG results are shown in Table JJ. Scotopic wave measurements that target rod-pathway function were made from the dark-adapted eye, whereas photopic wave measurement that target cone-pathway function were made from the light-adapted eye. The data illustrate that inhibition of NRL protected photoreceptor function in rd10 mice. Additionally, histological analysis of retina sections revealed a dramatic preservation of the photoreceptor layer following inhibition of NRL. Table JJ: Therapeutic Benefit of DT-000776 and DT-000430 in rd10 mice Each of compounds DT-000430, DT-000432, and DT-000776 was additionally tested in the P23H mouse model of retinitis pigmentosa. Based on ERG results and histological analyses, all three compounds demonstrated efficacy in the P23H model. Additionally, compound DT- 000776 was tested at doses of 0.3 ug, 1.0 ug, and 3.0 ug in the humanized NRL model on the rd10 background. Based on ERG results, DT-000776 demonstrated a therapeutic benefit at each dose, and in a dose-responsive manner. Example 14: Evaluation of Human NRL siRNAs in Non-Human Primates A non-GLP study was conducted in African green monkeys to evaluate the ocular distribution, pharmacodynamics, and tolerance of NRL siRNAs in non-human primates. Compounds DT-000432 and DT-000776 were selected for evaluation. PBS (vehicle) was used as a control treatment. A total of 12 animals were randomized into groups of two for treatment as follows: PBS, 75 µg DT-000432, 300 µg DT-000432, 18.75 µg DT-000776, 75 µg DT-000776, and 300 µg DT-000776. PBS or compound was administered by intravitreal injection (IVT) on Day 0 of the study. At Day 14 of the study, animals were euthanized, the eyes were enucleated, and 5 mm biopsy punches of tissue were collected from various regions of the eye. Each biopsy sample was prepared for RNA isolation. The level of NRL mRNA was measured by quantitative real-time PCR. The average percentage expression (i.e., average percent NRL remaining) from 22 to 24 tissue samples (11 to 12 biopsy punches from each of two animals per treatment) was calculated and is shown in Table KK. As is evident from the data in Table KK, both DT-000432 and DT-000776 reduced NRL mRNA in a dose-dependent manner. DT-000776 was more efficacious at the higher dose of 300 µg. Both compounds were distributed throughout the retina, and well-tolerated at all doses tested. Table KK: Dose-Dependent Reduction of NRL mRNA in African green monkeys Following IVT Injection of Conjugated NRL siRNAs

Claims

What is claimed: 1. A compound comprising an antisense strand and a sense strand hybridized to form a double-stranded nucleic acid, wherein each of the antisense strand and sense strands is 15 to 25 nucleotides in length, the nucleotide sequence of the antisense strand is at least 90% complementary to the nucleotide sequence of the NRL mRNA (SEQ ID NO: 1), and the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand.
2. The compound of claim 1, wherein each of the antisense strand and sense strands is 15 to 25 nucleotides in length, the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15 contiguous nucleotides of any one of nucleotides 501 to 563 of SEQ ID NO: 1, nucleotides 602 to 626 of SEQ ID NO: 1, nucleotides 623 to 654 of SEQ ID NO: 1, nucleotides 684 to 710 of SEQ ID NO: 1, nucleotides 741 to 765 of SEQ ID NO: 1, nucleotides 759 to 777 of SEQ ID NO: 1, nucleotides 882 to 909 of SEQ ID NO: 1, or nucleotides 1111 to 1133 of SEQ ID NO: 1, and the nucleotide sequence of the sense strand has no more than two mismatches to the nucleotide sequence of the antisense strand.
3. The compound of claim 1, wherein i. the antisense strand is 19 to 21 nucleotides in length; or ii. the antisense strand is 21 to 23 nucleotides in length.
4. The compound of claim 1, wherein i. the sense strand is 17 to 23 nucleotides in length; ii. the sense strand is 19 to 21 nucleotides in length; or iii. the sense strand is 21 to 23 nucleotides in length.
5. The compound of claim 1, wherein i. the double-stranded region is 19 nucleotide pairs in length; ii. the double-stranded region is 20 nucleotide pairs in length; or iii. the double-stranded region is 21 nucleotide pairs in length.
6. The compound of claim 1, wherein the nucleotide sequence of the sense strand has no more than one mismatch to the nucleotide sequence of the antisense strand.
7. The compound of claim 1, wherein the nucleotide sequence of the sense strand has no mismatches to the nucleotide sequence of the antisense strand.
8. The compound of claim 1, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 501 to 563 of SEQ ID NO: 1.
9. The compound of claim 1, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 602 to 626 of SEQ ID NO: 1.
10. The compound of claim 1, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 623 to 654 of SEQ ID NO: 1.
11. The compound of claim 1, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 684 to 710 of SEQ ID NO: 1.
12. The compound of claim 1, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or 25 contiguous nucleotides of nucleotides 741 to 765 of SEQ ID NO: 1.
13. The compound of claim 1, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, or 19 contiguous nucleotides of nucleotides 759 to 777 of SEQ ID NO: 1.
14. The compound of claim 1, wherein the nucleotide sequence of the antisense strand is at least 90% complementary to at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or 23 contiguous nucleotides of nucleotides 1111 to 1133 of SEQ ID NO: 1.
15. The compound of claim 1, wherein the antisense strand and the sense strand are not covalently linked.
16. The compound of claim 1, wherein at least one strand comprises a 3’ nucleotide overhang of one to five nucleotides.
17. The compound of claim 16, wherein the sense strand comprises the 3’ nucleotide overhang.
18. The compound of claim 16, wherein the antisense strand comprises the 3’ nucleotide overhang.
19. The compound of claim 16, wherein each nucleotide of the 3’ nucleotide overhang of the antisense strand is complementary to SEQ ID NO: 1.
20. The compound of claim 16, wherein the 3’ nucleotide overhang is two nucleotides in length.
21. The compound of claim 1, wherein each nucleotide of the antisense strand forming the double-stranded region is a modified nucleotide.
22. The compound of claim 1, wherein each nucleotide of the sense strand forming the double-stranded region is a modified nucleotide.
23. The compound of claim 21, wherein the modified nucleotide comprises one or more of a modified sugar moiety, a modified internucleotide linkage, and a 5’-terminal modified phosphate group.
24. The compound of claim 23, wherein the modified nucleotide comprising a modified sugar moiety is selected from a 2’-fluoro nucleotide, a 2’-O-methyl nucleotide, a 2’-O-methoxyethyl nucleotide, and a bicyclic sugar nucleotide.
25. The compound of claim 24, wherein the modified internucleotide linkage is a phosphorothioate internucleotide linkage.
26. The compound of claim 25, wherein the first two internucleotide linkages at the 5’ terminus of the sense strand and the last two internucleotide linkages at the 3’ terminus of the sense strand are phosphorothioate internucleotide linkages.
27. The compound of claim 26, wherein the first two internucleotide linkages at the 5’ terminus of the antisense strand and the last two internucleotide linkages at the 3’ terminus of the antisense strand are phosphorothioate internucleotide linkages.
28. The compound of claim 1, wherein the compound comprises a ligand covalently linked to the double-stranded nucleic acid.
29. The compound of claim 28, wherein the compound has the structure: wherein A is the double-stranded nucleic acid; wherein t is an integer from 1 to 5; L3 and L4 are independently a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, -C(O)N(R24)-, -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O-P(S)(NR23R24)-N-, -O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; L5 is -L5A-L5B-L5C-L5D-L5E-; L6 is -L6A-L6B-L6C-L6D-L6E-; R1 and R2 are independently unsubstituted C1-C25 alkyl, wherein at least one of R1 and R2 is unsubstituted C9-C19 alkyl; R3 is hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, –N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L5A, L5B, L5C, L5D, L5E, L6A, L6B, L6C, L6D, and L6E are independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, –C(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; and each R23, R24 and R25 is independently hydrogen or unsubstituted C1-C10 alkyl.
30. The compound of claim 29, wherein (i) t is 1; (ii) t is 2; or (iii) t is 3.
31. The compound of claim 29, wherein A is the sense strand of the double- stranded nucleic acid.
32. The compound of claim 31, wherein -L3-L4- , the phosphate group of -L3-L4- is attached to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, , L5 is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C15 alkyl, and R2 is unsubstituted unbranched C15 alkyl.
33. The compound of claim 31, wherein -L3-L4- is , the phosphate group of -L3-L4- to the 3’ carbon of the 3’ terminal nucleotide of the sense strand, , L5 is -NHC(O)-, R3 is hydrogen, R1 is unsubstituted unbranched C13 alkyl, and and R2 is unsubstituted unbranched C13 alkyl.
34. The compound of claim 31, wherein the compound is selected from DT- 000429, DT-000430, DT-000431, DT-000432, DT-000735, DT-000736, DT-000737, DT-000738, DT-000776, DT-000777, DT-000778, DT-000785, DT-000786, DT-000787, DT-000828, DT-000829, DT-000830, DT-000831, and DT-000832.
35. The compound of claim 31, wherein the compound is DT-000430.
36. The compound of claim 31, wherein the compound is DT-000432.
37. The compound of claim 31, wherein the compound is DT-000776.
38. The compound of claim 31, wherein the compound is DT-001373.
39. The compound of claim 31, wherein the compound is DT-001374.
40. The compound of claim 31, wherein the compound is DT-001374.
41. The compound of claim 31, wherein the compound is DT-001386.
42. The compound of claim 1, wherein the compound is present as a pharmaceutical salt.
43. The compound of claim 42, wherein the salt is a sodium salt.
44. The compound of claim 1, wherein the compound is present in a pharmaceutically acceptable diluent.
45. The compound of claim 44, wherein the pharmaceutically acceptable diluent is a sterile aqueous solution.
46. The compound of claim 45, wherein the sterile aqueous solution is a sterile saline solution.
47. A pharmaceutical composition comprising the compound of claim 1.
48. A method of inhibiting the expression of neural retina leucine zipper (NRL) mRNA in a cell, comprising contacting the cell with a compound of claim 1, thereby inhibiting the expression of NRL mRNA in the cell.
49. The method of claim 48, wherein the cell is a photoreceptor cell.
50. The method of claim 49, wherein the cell is in vitro.
51. The method of claim 49, wherein the cell is in vivo.
52. A method of inhibiting the expression of neural retina leucine zipper (NRL) in a subject, comprising administering to the subject an effective amount of a compound of claim 1, thereby inhibiting the expression of neural retina leucine zipper (NRL) mRNA.
53. A method of treating retinitis pigmentosa, comprising administering to a subject in need thereof an effective amount of a compound of claim 1.
54. The method of claim 53, wherein prior to administration of the compound, the subject has been diagnosed as having retinitis pigmentosa.
55. The method of claim 54, wherein the subject is diagnosed as having retinitis pigmentosa by the presence of one or more of: a family history of retinitis pigmentosa; decreased visual acuity; abnormal retinal morphology; the presence of nyctalopia; visual field constriction; a reduced response to light stimulus; and retinal pigmentation abnormalities.
56. The method of claim 55, wherein the administration is selected from intraocular administration and topical administration.
57. The method of claim 56, wherein the intraocular administration is subconjunctival administration, intravitreal administration, retrobulbar administration, or intracameral administration.
58. The method of claim 53, wherein the administration improves or slows the progression of one or more indicators of retinitis pigmentosa in the subject, wherein the one or more indicators is selected from visual acuity, visual acuity, retinal morphology, nyctalopia, visual field constriction, response to a light stimulus, and retinal pigmentation.
59. The method of claim 58, wherein response to a light stimulus is measured by electroretinography.
60. The method of claim 53, comprising administering at least one additional therapy to the subject.
61. Use of the compound of claim 1 in therapy.
62. Use of the compound of claim 1 for the treatment of retinitis pigmentosa.
63. Use of the pharmaceutical composition of claim 47 for the treatment of retinitis pigmentosa.
EP22873810.0A 2021-09-21 2022-09-20 Compounds targeting nrl for the treatment of retinitis pigmentosa Pending EP4405477A1 (en)

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