WO2022150369A1 - Composés pour le traitement de la maladie de batten - Google Patents
Composés pour le traitement de la maladie de batten Download PDFInfo
- Publication number
- WO2022150369A1 WO2022150369A1 PCT/US2022/011291 US2022011291W WO2022150369A1 WO 2022150369 A1 WO2022150369 A1 WO 2022150369A1 US 2022011291 W US2022011291 W US 2022011291W WO 2022150369 A1 WO2022150369 A1 WO 2022150369A1
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- WIPO (PCT)
- Prior art keywords
- synthetic oligonucleotide
- oligonucleotide
- sna
- cln3
- nucleic acid
- Prior art date
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- C—CHEMISTRY; METALLURGY
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- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
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Definitions
- Batten disease refers to a collective group of rare degenerative nervous system disorders called neuronal ceroid lipofuscinoses (NCLs). Juvenile-onset Batten disease (also known as CLN3 Batten disease) is the most common of these NCLs. A majority of CLN3 Batten disease patients harbor deletion of exons 7 and 8 from the neuronal ceroid- lipofuscinosis 3 lysosomal/endosomal transmembrane protein, battenin ( CLN3 ) gene. This loss-of-function mutation causes a frameshift, resulting in nonsense mediated decay of the CLN3 mRNA and a lack of CLN3 protein.
- NCL neuronal ceroid lipofuscinosis
- the compounds, methods and pharmaceutical compositions provided herein affect the expression of splicing isoforms of CLN3 RNA, such as by increasing the expression of alternatively spliced isoforms.
- the compounds, methods and pharmaceutical compositions disclosed herein increase the amount of functional CLN3 protein in a cell or animal.
- synthetic oligonucleotides and pharmaceutically acceptable salts thereof are provided herein.
- a synthetic oligonucleotide comprises a nucleic acid sequence 10 to 30 nucleosides in length that is complementary to a region of at least 10 contiguous nucleotides of a CLN3 sequence as set forth in SEQ ID NO: 2, the synthetic oligonucleotide comprises at least one 2’-O-methoxyethyl (2’-MOE) or locked nucleic acid (LNA) modified nucleoside, and each cytidine residue of the synthetic oligonucleotide is a 5- methyl cytidine and each thymidine residue of the synthetic oligonucleotide is a 5-methyl uridine.
- 2’-MOE 2’-O-methoxyethyl
- LNA locked nucleic acid
- the CLN3 sequence is a human CLN3 pre-mRNA sequence or a human CLN3 genomic sequence.
- the region of at least 10 contiguous nucleotides is within intron 4, intron 4 and exon 5, exon 5, exon 5 and intron 5, intron 5, intron 5 and exon 6, exon 6, exon 6 and intron 6, intron 6, intron 8, intron 8 and exon 9, exon 9, exon 9 and intron 9, or intron 9 of a human CLN3 sequence.
- the nucleic acid sequence is complementary to a region of at least 18 contiguous oligonucleotides of the CLN3 sequence. In some embodiments, the nucleic acid sequence is complementary to a region of at least 20 contiguous oligonucleotides of the CLN3 sequence.
- the nucleic acid sequence is 15 to 22 nucleosides in length. In some embodiments, the nucleic acid sequence is 20 nucleosides in length.
- the synthetic oligonucleotide comprises a molecular species.
- the molecular species is indirectly attached to a nucleotide of the synthetic oligonucleotide.
- the molecular species is indirectly attached to the nucleotide at the 3’ end of the synthetic oligonucleotide.
- the molecular species is indirectly attached to the nucleotide at the 5’ end of the synthetic oligonucleotide.
- the molecular species comprises or consists of a cholesterol or a tocopherol. In some embodiments, the molecular species comprises or consists of (N- cholesteryl-3-aminopropyl)-triethyleneglycol-glyceryl-l-O-phosphodiester (CholTEG).
- the synthetic oligonucleotide comprises a spacer.
- the spacer comprises or consists of oligoethylene.
- the oligoethylene is hexaethyleneglycol (HEG).
- the spacer comprises or consists of two HEGs.
- the spacer comprises or consists of HEG and triethyleneglycol (TEG).
- the molecular species is indirectly attached to the nucleotide of the synthetic oligonucleotide through the spacer.
- the synthetic oligonucleotide comprises at least one phosphorothioate internucleoside linkage. In some embodiments, the synthetic oligonucleotide comprises two or more phosphorothioate internucleoside linkages, or each intemucleoside linkage of the synthetic oligonucleotide is a phosphorothioate internucleoside linkage.
- the synthetic oligonucleotide comprises at least one phosphodiester intemucleoside linkage. In some embodiments, the synthetic oligonucleotide comprises two or more phosphodiester intemucleoside linkages, or each intemucleoside linkage of the synthetic oligonucleotide is a phosphodiester intemucleoside linkage.
- the synthetic oligonucleotide comprises at least two nucleotide modifications.
- the at least two nucleotide modifications are selected from the group consisting of a 2’-O-methyl modification (2’-O-Me), a 2’-MOE modification, a 2’-O-methoxyethoxy-5-methyl (5-Me-MOE) modification, an LNA modification, a 5- methyl (5-Me) modification, a 7-deaza modification, and a 7-deaza-2’ -O-methyl (7deazaOM) modification.
- At least two nucleotides of the synthetic oligonucleotide comprise 2’-MOE modifications. In some embodiments, each nucleotide of the synthetic oligonucleotide comprises a 2’-MOE modification.
- the synthetic oligonucleotide comprises the nucleic acid sequence of any one of SEQ ID NO: 11-772.
- an SNA comprises a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence 10 to 30 nucleotides in length that is complementary to a region of at least 10 contiguous nucleotides of a CLN3 sequence as set forth in SEQ ID NO: 1.
- the synthetic oligonucleotide comprises at least one 2’-O-methoxyethyl (2’- MOE) or locked nucleic acid (LNA) modified nucleoside.
- each cytidine residue of the synthetic oligonucleotide is a 5-methyl cytidine. In some embodiments, each thymidine residue of the synthetic oligonucleotide is a 5-methyl uridine.
- the synthetic oligonucleotide is a synthetic oligonucleotide disclosed herein.
- the synthetic oligonucleotide comprises a molecular species.
- the molecular species is indirectly attached to a nucleotide of the synthetic oligonucleotide.
- the molecular species is indirectly attached to the nucleotide at the 3’ end of the synthetic oligonucleotide.
- the molecular species is indirectly attached to the nucleotide at the 5’ end of the synthetic oligonucleotide.
- the molecular species comprises or consists of a cholesterol or a tocopherol. In some embodiments, the molecular species comprises or consists of (N- cholesteryl-3-aminopropyl)-triethyleneglycol-glyceryl-l-O-phosphodiester (CholTEG).
- the synthetic oligonucleotide is anchored to the surface of the core through the molecular species.
- the core is a hollow core or solid core.
- the hollow core is a liposome core.
- the liposome core comprises or consists of l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC).
- the oligonucleotide shell comprises or consists of 20 to 50 synthetic oligonucleotides. In some embodiments, the oligonucleotide shell comprises or consists of 25 to 35 synthetic oligonucleotides. In some embodiments, the oligonucleotide shell comprises or consists of 30 or about 30 synthetic oligonucleotides.
- the core is a liposome core comprising lipid molecules
- the synthetic oligonucleotides of the oligonucleotide shell are at a molar ratio of or about 50 to 1 of lipid molecules to synthetic oligonucleotides.
- the oligonucleotide shell comprises a second synthetic oligonucleotide comprising a second nucleic acid sequence 10 to 30 nucleotides in length that is complementary to a second region of at least 10 contiguous nucleotides of a CLN3 sequence as set forth in SEQ ID NO: 1.
- the second synthetic oligonucleotide is a synthetic oligonucleotide disclosed herein.
- compositions are provided herein.
- a pharmaceutical composition comprises a synthetic oligonucleotide disclosed herein or pharmaceutically acceptable salt thereof.
- a pharmaceutical composition comprises an SNA disclosed herein.
- a method of producing alternatively spliced CLN3 RNA in a cell comprises contacting a cell comprising a CLN3 gene and/or a CLN3 gene product with a synthetic oligonucleotide disclosed herein, an SNA disclosed herein, or a pharmaceutical composition disclosed herein, to produce alternatively spliced CLN3 RNA in the cell.
- the alternatively spliced CLN3 RNA lacks exon 5, exon 6, and/or exon 9.
- the cell is a neuronal cell, a fibroblast, an astrocyte, a microglial cell, or a cell of the eye.
- the cell of the eye is a retinal cell.
- a method of treating a disease or disorder in a subject comprises administering to a subject an effective amount of a synthetic oligonucleotide disclosed herein, an SNA disclosed herein, or a pharmaceutical composition disclosed herein, in order to treat the disease or disorder in the subject.
- the disease or disorder is an inherited disease or disorder. In some embodiments, the disease or disorder is a neurodegenerative disease or disorder. In some embodiments, the disease or disorder is a neuronal ceroid lipofuscinosis (NCL). In some embodiments, the disease or disorder is Batten disease, juvenile NCL, or CLN3 Batten disease.
- NCL neuronal ceroid lipofuscinosis
- administering the synthetic oligonucleotide, the SNA, or the pharmaceutical composition to the subject ameliorates or eliminates one or more symptoms or conditions associated with the disease or disorder in the subject.
- the one or more symptoms or conditions are visual impairment, retinal degeneration, intellectual disability, impaired cognitive function, speech impairment, seizures, muscle rigidity or stiffness, hypokinesia, stooped posture, arrhythmia, and/or impaired motor function.
- the method comprises the administration of a second therapeutic agent.
- 2’-modified or “2’-substituted” refers to a nucleoside comprising a sugar with a substituent group at the 2’ carbon position other than H or OH.
- bicyclic nucleoside refers to a bicyclic nucleoside comprising a furanose ring comprising a bridge connecting two carbon atoms of the furanose ring connects the 2’ carbon atom and the 4’ carbon atom of the sugar ring. Nucleoside modifications are discussed in further detail below.
- 5-methyl cytosine means a cytosine modified with a methyl group attached to the 5 position.
- a 5-methyl cytosine is a modified nucleobase. Modified nucleobases are discussed in further detail below.
- “about” means within ⁇ 10% of a value.
- statements in accordance with “about 70% inhibition” indicate that the referenced inhibition is within a range of 60% and 80%.
- statements in accordance with “about 100” indicate values within a range of 90 to 110.
- administering refers to routes of introducing a compound or composition provided herein to an individual to perform its intended function.
- An example of a route of administration that can be used includes, but is not limited to parenteral administration, such as subcutaneous, intravenous, or intramuscular injection or infusion, intravitreal administration, intracistema magna administration, or intrathecal administration. Administration details are discussed in further detail below.
- administered concomitantly means administration of two agents in any manner in which the pharmacological effects of both are manifest in the patient at the same time. Concomitant administration does not require that both agents be administered in a single pharmaceutical composition, in the same dosage form, by the same route of administration, or in parallel. Co-administration encompasses both parallel and sequential administration. The effects of both agents need not manifest themselves at the same time. The effects need only be overlapping for a period of time and need not be coextensive.
- alternative splicing refers to the use of different combinations of exons within gene products generated from a given transcript to generate multiple mRNA transcripts from a single gene.
- alternative splicing may result in the production of one mRNA molecule comprising exons 1, 2, 3, 4, and 6 of a given gene and another mRNA molecule having exons 1, 2, 3, 5, and 6 of the gene.
- “ameliorate” in reference to a treatment means improvement or lessening in at least one indicator, sign or symptom of a disease, disorder or condition relative to the same indicator, sign or symptom in the absence of the treatment.
- amelioration is the reduction in the severity or frequency of an indicator, sign or symptom or the delayed onset or slowing of progression in the severity or frequency of a symptom.
- the symptom or hallmark includes progressive loss of motor function, seizures, vision loss, and loss of cognitive function. Symptoms and their amelioration are discussed in further detail below.
- animal means a human or non-human animal.
- an “antisense compound” refers to a compound comprising an oligonucleotide and optionally one or more additional features, such as a conjugate group or terminal group.
- antisense compounds include single-stranded and double- stranded compounds, such as, oligonucleotides, ribozymes, siRNAs, shRNAs, ssRNAs, and occupancy-based compounds.
- antisense inhibition refers to reduction of one or more levels of a target nucleic acid facilitated by or corresponding to the presence of an antisense compound complementary to the target nucleic acid compared to target nucleic acid levels in the absence of the antisense compound.
- antisense mechanisms are all those mechanisms involving hybridization of a compound with target nucleic acid, wherein the outcome or effect of the hybridization is either target degradation or target occupancy with concomitant stalling of the cellular machinery involving, for example, transcription or splicing.
- antisense oligonucleotide refers to an oligonucleotide having a nucleobase sequence that is complementary or sufficiently complementary to a target nucleic acid or region or segment thereof. In certain embodiments, an antisense oligonucleotide is specifically hybridizable to a target nucleic acid or region or segment thereof. Antisense oligonucleotides are discussed in further detail below.
- bicyclic nucleoside or “BNA” refers to a nucleoside comprising a bicyclic sugar moiety.
- bicyclic sugar and “bicyclic sugar moiety” refer to a modified sugar moiety comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure.
- the first ring of the bicyclic sugar moiety is a furanosyl moiety.
- the bicyclic sugar moiety does not comprise a furanosyl moiety.
- LNA is a bicyclic nucleoside. Bicyclic sugars and nucleosides are discussed in further detail below.
- CLN3 or “a CLN3 sequence” or “CLN3 protein” refers to the ceroid-lipofuscinosis, neuronal 3 (CLN3) gene or a nucleic acid sequence or polypeptide/protein product thereof. CLN3 is also known as CLN3 lysosomal/endosomal transmembrane protein, Battenin, Batten Disease Protein, BTS, JNCL, and BTN1.
- the genomic sequence of human CLN3 is set forth in RefSeqGene (LRG_689) on chromosome 16, NCBI Reference Sequence: NG_008654.2 (SEQ ID NO: 1).
- the human CLN3 gene comprises nucleotides 5,001-30,650 of NCBI Reference Sequence: NG_008654.2 (SEQ ID NO: 1), and is provided as SEQ ID NO: 2. Additional human CLN3 sequences are provided as SEQ ID NO: 3-10 and the murine CLN3 gene sequence is provided as SEQ ID NO: 773. CLN3 and CLN3 sequences are discussed in further detail below.
- complementary in reference to an oligonucleotide means that at least 70% of the nucleobases of the oligonucleotide or one or more regions thereof and the nucleobases of another nucleic acid or one or more regions thereof are capable of hydrogen bonding with one another when the nucleobase sequence of the oligonucleotide and the other nucleic acid are aligned in opposing directions.
- Complementary nucleobases means nucleobases that are capable of forming hydrogen bonds with one another.
- Complementary nucleobase pairs include adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine and guanine (G), 5-methyl cytosine (5-Me-C) and guanine (G).
- Complementary oligonucleotides and/or nucleic acids need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated.
- “fully complementary” or “100% complementary” in reference to oligonucleotides means that oligonucleotides are complementary to another oligonucleotide or nucleic acid at each nucleoside of the oligonucleotide.
- an antisense compound and its target are complementary to each other when a sufficient number of corresponding positions in each molecule are occupied by nucleobases that can bond with each other to allow stable association between the antisense compound and the target.
- nucleobases that can bond with each other to allow stable association between the antisense compound and the target.
- antisense compounds may comprise up to about 20% nucleotides that are mismatched (i.e., are not nucleobase complementary to the corresponding nucleotides of the target).
- the antisense compounds contain no more than about 15%, more preferably not more than about 10%, most preferably not more than 5% or no mismatches.
- nucleobase complementary or otherwise do not disrupt hybridization e.g., universal bases.
- nucleobase complementary or otherwise do not disrupt hybridization e.g., universal bases.
- compounds provided herein are at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% complementary to a target nucleic acid. Sequence complementarity is discussed in further detail below.
- oligonucleotide refers to nucleosides, nucleobases, sugar moieties, or intemucleoside linkages that are immediately adjacent to each other.
- contiguous nucleobases refers to nucleobases that are immediately adjacent to each other in a sequence.
- “differently modified” means chemical modifications or chemical substituents that are different from one another, including absence of modifications.
- an MOE nucleoside and an unmodified DNA nucleoside are “differently modified,” even though the DNA nucleoside is unmodified.
- DNA and RNA are “differently modified,” even though both are naturally-occurring unmodified nucleosides. Nucleosides that are the same but for comprising different nucleobases are not differently modified.
- nucleoside comprising one 2’-OMe modified sugar and one unmodified adenine nucleobase and a nucleoside comprising one 2’-OMe modified sugar and one unmodified thymine nucleobase are not differently modified. Chemical modifications are discussed in further detail below.
- dose means a specified quantity of a pharmaceutical agent provided in a single administration, or in a specified time period.
- a dose may be administered in one, two, or more boluses, tablets, or injections.
- the desired dose requires a volume not easily accommodated by a single injection, therefore, two or more injections may be used to achieve the desired dose.
- the pharmaceutical agent is administered by infusion (e.g., intravenous infusion) over an extended period of time or continuously. Doses may be stated as the amount of pharmaceutical agent per hour, day, week, or month.
- dose regimen is a combination of doses designed to achieve one or more desired effects.
- effective amount means the amount of active pharmaceutical agent sufficient to effectuate a desired physiological outcome in an individual in need of the agent.
- the effective amount may vary among individuals depending on the health and physical condition of the individual to be treated, the taxonomic group of the individuals to be treated, the formulation of the composition, assessment of the individual’s medical condition, and other relevant factors.
- efficacy means the ability to produce a desired effect.
- exon refers to a region of a primary RNA transcript that remains in the mature RNA when it reaches the cytoplasm. Exons are “spliced” together to form the mature mRNA sequence. Intron-exon junctions are also referred to as “splice sites” with the 5' side of the junction often called the “5' splice site,” or “splice donor site” and the 3' side the “3' splice site” or “splice acceptor site.” “Cryptic” splice sites are those which are less often used but may be used when the “normal” splice site is blocked or unavailable. A splice modulator can be used to force a primary RNA transcript to use a cryptic splice site and generate an alternatively spliced RNA transcript.
- expression includes all the functions by which a gene’s coded information is converted into structures present and operating in a cell, tissue or animal.
- Such structures include, but are not limited to, the products of transcription and translation.
- hybridization means the pairing or annealing of complementary oligonucleotides and/or nucleic acids. While not limited to a particular mechanism, the most common mechanism of hybridization involves hydrogen bonding, which may be Watson- Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases.
- internucleotide linkage and “internucleoside linkage” refer to the covalent linkage between adjacent nucleosides in an oligonucleotide.
- modified internucleotide linkage and “modified intemucleoside linkage” refer to any such linkage other than a phosphodiester (PO) linkage.
- Phosphorothioate internucleotide linkage or (PS) is a modified intemucleotide linkage in which one of the non-bridging oxygen atoms of a phosphodiester intemucleotide linkage is replaced with a sulfur atom.
- an intemucleotide linkage is a phosphotriester linkage, or phosphorothioate triester linkage.
- an intemucleotide linkage is one of, e.g., PNA (peptide nucleic acid) or PMO (phosphorodiamidate Morpholino oligomer) linkage.
- a modified intemucleotide linkage is a non-negatively charged intemucleotide linkage.
- a modified intemucleotide linkage is a neutral intemucleotide linkage. It is understood by a person of ordinary skill in the art that an intemucleotide linkage may exist as an anion or cation at a given pH due to the existence of acid or base moieties in the linkage. Internucleotide/intemucleoside linkages are discussed in further detail below.
- intron refers to a region of a primary RNA transcript that is not included in the mature mRNA. Introns are removed during RNA splicing and are retained in the nucleus.
- linked nucleosides means adjacent nucleosides linked together by an internucleoside linkage.
- linker refers to any chemical moiety which connects one chemical moiety to another.
- a linker can be bivalent or trivalent or more, depending on the number of chemical moieties the linker connects.
- a linker is a moiety which connects one oligonucleotide to another oligonucleotide in a multimer.
- a linker is a moiety optionally positioned at the 3’ or 5’ end of the oligonucleotide.
- a linker in an oligonucleotide, is a lipophilic moiety that facilitates the incorporation of an oligonucleotide into or onto the external surface of a core.
- the linker comprises or consists of a cholesterol.
- the linker comprises or consists of (N-cholesteryl-3-aminopropyl)-triethyleneglycol-glyceryl-l-O-phosphodiester (CholTEG). Linkers are discussed in further detail below.
- locked nucleic acid or “LNA” or “LNA nucleoside” refers to a modified nucleoside which comprises a bridging moiety linking the 2’ and 4’ carbons of the ribose sugar ring (also referred to as a “2’-4’ bridge”), which restricts or locks the conformation of the ribose ring.
- LNA is an example of BNA.
- Non-limiting, exemplary LNA nucleosides are disclosed in WO 1999/014226, WO 2000/66604, WO 1998/039352, WO 2004/046160, WO 2000/047599, WO 2007/134181, WO 2010/077578, WO 2010/036698, WO 2007/090071, WO 2009/006478, WO 2011/156202, WO 2008/154401, WO 2009/067647, and WO 2008/150729, the contents of each of which are incorporated herein by reference in their entireties. LNA modifications are discussed in further detail below.
- mismatch or “non-complementary” means a nucleobase of a first oligonucleotide that is not complementary with the corresponding nucleobase of a second oligonucleotide or target nucleic acid molecule when the first and second oligonucleotide are aligned.
- nucleobases including but not limited to a universal nucleobase, inosine, and hypoxanthine, are capable of hybridizing with at least one nucleobase but are still mismatched or non-complementary with respect to nucleobase to which it hybridized.
- a nucleobase of a first oligonucleotide that is not capable of hybridizing to the corresponding nucleobase of a second oligonucleotide or target nucleic acid when the first and second oligonucleotides are aligned is a mismatch or non-complementary nucleobase.
- modulate refers to changing or adjusting a feature in a cell, tissue, organ or organism.
- modulating CLN3 can mean to increase or decrease the level of CLN3 RNA and/or CLN3 protein in a cell, tissue, organ or organism.
- a “modulator” effects the change in the cell, tissue, organ or organism.
- an SNA compound can be a modulator that increases the amount of alternatively spliced CLN3 RNA and/or functional CLN3 protein in a cell, tissue, organ or organism.
- modulation of splicing refers to altering the processing of a pre- mRNA transcript such that the spliced mRNA molecule contains either a different combination of exons as a result of exon skipping or exon inclusion, a deletion of one or more exons, or an additional sequence not normally found in the spliced mRNA (e.g., intron sequence).
- modulation of splicing refers to altering splicing of CLN3 RNA under certain conditions or in response to certain events whereby a shortened version of CLN3 mRNA is produced in a cell tissue, organ or organism.
- a “morpholino oligomer” refers to a polymeric molecule having a backbone which supports bases capable of hydrogen bonding to typical oligonucleotides, wherein the polymer lacks a ribose sugar moiety, and more specifically a ribose sugar backbone linked by phosphodiester bonds which is typical of naturally occurring oligonucleotides and nucleosides, but instead contains a ring nitrogen with coupling through the ring nitrogen.
- Exemplary structures of morpholino oligonucleotides are described, for example, in Hudziak et ah, Antisense Nucleic Acid Drug Dev. 6: 267-272 (1996) and Summerton and Weller, Antisense Nucleic Acid Drug Dev. 7: 187-195 (1997), the contents of each of which are incorporated herein by reference in their entireties.
- motif means the pattern of modified sugar moieties, nucleobases, and/or intemucleotide linkages, in an oligonucleotide.
- neurodegenerative disease refers to a condition marked by progressive loss of function or structure of components of the nervous system, including loss of motor function and death of neurons.
- the neurodegenerative disease is a neuronal ceroid lipofuscinosis (NCL).
- the neurodegenerative disease is CLN3 Batten disease. Neurodegenerative diseases are discussed in further detail below.
- non-bicyclic modified sugar or “non-bicyclic modified sugar moiety” means a modified sugar moiety that comprises a modification, such as a substituent, that does not form a bridge between two atoms of the sugar to form a second ring.
- Sugar modifications are discussed in further detail below.
- nucleic acid refers to molecules composed of linked nucleosides. Nucleic acids include, but are not limited to, ribonucleic acids (RNA), deoxyribonucleic acids (DNA), single- stranded nucleic acids, and double- stranded nucleic acids. Nucleic acids are discussed in further detail below.
- nucleobase refers to an unmodified nucleobase or a modified nucleobase.
- an “unmodified nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), or guanine (G).
- a “modified nucleobase” is a group of atoms other than unmodified A, T, C, U, or G capable of pairing with at least one unmodified nucleobase. Examples of modified nucleobases include but are not limited to 5-methyl cytosine, 7-deaza guanosine, and 7-deaza deoxyguanosine.
- a universal base is a modified nucleobase that can pair with any one of the five unmodified nucleobases. Modified and unmodified nucleobases are discussed in further detail below.
- nucleobase sequence or “nucleic acid sequence” refers to the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or linkage modification(s).
- nucleoside refers to a compound comprising a nucleobase and a sugar moiety.
- the nucleobase and sugar moiety are each, independently, unmodified or modified.
- modified nucleoside refers to a nucleoside comprising a modified nucleobase and/or a modified sugar moiety.
- Modified nucleosides include abasic nucleosides, which lack a nucleobase.
- Linked nucleosides are nucleosides that are connected in a contiguous sequence (i.e., no additional nucleosides are present between those that are linked). Nucleosides are discussed in further detail below.
- oligomeric compound refers to an oligonucleotide and optionally one or more additional features, such as a conjugate group or terminal group.
- An oligomeric compound may be paired with a second oligomeric compound that is complementary to the first oligomeric compound or may be unpaired.
- a “single- stranded oligomeric compound” is an unpaired oligomeric compound.
- oligomeric duplex means a duplex formed by two oligomeric compounds having complementary nucleobase sequences.
- oligomeric compound of an oligomeric duplex may be referred to as a “duplexed oligomeric compound.”
- an “oligonucleotide” refers to a strand of nucleosides ⁇ i.e., molecules comprising a sugar (e.g., ribose or deoxyribose) linked to an exchangeable organic base, such as pyrimidine (e.g., cytosine (C), thymine (T) or uracil (U)) or a purine (e.g., adenine (A) or guanine (G))) which are linked, having a length of typically between eight and 100 nucleobases.
- pyrimidine e.g., cytosine (C), thymine (T) or uracil (U)
- purine e.g., adenine (A) or guanine (G)
- Each nucleoside and intemucleoside linkage of an oligonucleotide may be modified or unmodified, relative to a reference nucleoside sequence.
- a “modified oligonucleotide” refers to an oligonucleotide wherein at least one nucleoside or intemucleoside linkage is modified relative to a naturally-occurring strand of linked nucleosides.
- an “unmodified oligonucleotide” refers to an oligonucleotide that does not comprise any nucleoside modifications or internucleotide linkage modifications. Oligonucleotides are discussed in further detail below.
- parenteral administration means administration through injection or infusion.
- Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, intravitreal administration, intracranial administration, intrathecal administration, intracistema magna administration, and intracerebroventricular administration.
- pharmaceutical agent refers to a compound that provides a therapeutic benefit when administered to a subject.
- pharmaceutical composition refers to a mixture of substances suitable for administering to a subject.
- a pharmaceutical composition may comprise an oligomeric compound and a sterile aqueous solution (i.e., a pharmaceutically acceptable carrier).
- a pharmaceutical composition shows activity in free uptake assays in certain cell lines. Pharmaceutical agents and compositions are discussed in further detail below.
- pharmaceutically acceptable carrier or diluent refers to any substance suitable for use in administering to an animal. Certain such carriers enable pharmaceutical compositions to be formulated as, for example, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspension and lozenges for the oral ingestion by a subject.
- a pharmaceutically acceptable carrier or diluent is sterile water, sterile saline, sterile buffer solution or sterile artificial cerebrospinal fluid.
- phosphorothioate linkage refers to a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced with a sulfur atom.
- a phosphorothioate intemucleoside linkage is a modified intemucleoside linkage. Intemucleoside linkages are discussed in further detail below.
- prevent refers to delaying or forestalling the onset, development or progression of a disease, disorder, or condition for a period of time from minutes to indefinitely.
- a “region” of a nucleic acid sequence is a portion of the nucleic acid having at least one identifiable structure, function, or characteristic, including a particular sequence.
- RNA refers to an RNA transcript that encodes a protein and includes pre-mRNA and mature mRNA unless otherwise specified.
- side effects refers to physiological diseases and/or conditions attributable to a treatment other than the desired effects.
- side effects include injection site reactions, liver function test abnormalities, renal function test abnormalities, liver toxicity, renal toxicity, central nervous system abnormalities, myopathies, and malaise.
- increased aminotransferase levels in serum may indicate liver toxicity or liver function abnormality
- increased bilirubin may indicate liver toxicity or liver function abnormality
- changes in glomerular filtration rate may represent renal toxicity or renal impairment.
- single- stranded in reference to a given nucleic acid compound means the compound has only one oligonucleotide or nucleic acid strand.
- a single- stranded compound may be capable of binding to a complementary compound to form a duplex.
- spacer refers to a group of atoms that connect two moieties, such as a linker and an oligonucleotide.
- a spacer comprises or consists of an oligoethylene.
- the oligoethylene is hexaethyleneglycol (HEG).
- the spacer comprises or consists of two or more connected HEG molecules (e.g., two HEG molecules covalently bound via a phosphodiester bond).
- the spacer comprises or consists of hexa(ethyleneglycol)phosphodiester- hexa(ethyleneglycol)phosphodiester (HEG-HEG).
- two moieties are indirectly attached to one another through a spacer.
- a spacer comprises or consists of one or more nucleosides, or does not comprise nucleosides. Spacers are discussed in further detail below.
- spherical nucleic acid or “SNA” refers to a three-dimensional arrangement of oligonucleotides comprising an oligonucleotide shell radially oriented around or on the exterior of a core. SNAs are discussed in further detail below.
- sugar moiety refers to an unmodified sugar moiety or a modified sugar moiety.
- unmodified sugar moiety means a 2’-OH(H) ribosyl moiety, as found in RNA (an “unmodified RNA sugar moiety”), or a 2’-H(H) deoxyribosyl sugar moiety, as found in DNA (an “unmodified DNA sugar moiety”).
- Unmodified sugar moieties have one hydrogen at each of the 1’, 3’, and 4’ positions, an oxygen at the 3’ position, and two hydrogens at the 5’ position.
- modified sugar moiety or “modified sugar” means a modified furanosyl sugar moiety or a sugar surrogate. Sugar moieties are discussed in further detail below.
- sugar surrogate refers to a modified sugar moiety having other than a furanosyl moiety that can link a nucleobase to another group, such as an intemucleoside linkage, conjugate group, or terminal group in an oligonucleotide.
- Modified nucleosides comprising sugar surrogates can be incorporated into one or more positions within an oligonucleotide and such oligonucleotides are capable of hybridizing to complementary oligomeric compounds or target nucleic acids.
- modified nucleosides include those where the ribose ring structure is modified, e.g.
- HNA hexose ring
- LNA ribose ring
- UNA unlinked ribose ring which typically lacks a bond between the 2’ carbon and 3’ carbon
- Other sugar modified nucleosides include, for example, bicyclohexose nucleic acids (WO2011/017521) or tricyclic nucleic acids (WO2013/154798). Modified nucleosides also include nucleosides where the sugar moiety is replaced with a non- sugar moiety, for example in the case of peptide nucleic acids (PNA), or morpholino nucleic acids.
- PNA peptide nucleic acids
- symptom or “hallmark” refers to any physical feature or test result that indicates the existence or extent of a disease or disorder.
- a symptom is apparent to a subject or to a medical professional examining or testing said subject.
- a hallmark is apparent upon invasive diagnostic testing, including, but not limited to, post-mortem tests.
- “synergy” or “synergize” mean an effect of a combination of two or more components that is greater than the additive effects of each component alone at the same doses.
- target gene refers to a gene encoding a target molecule.
- targeting means the specific hybridization of a compound to a target nucleic acid in order to induce a desired effect.
- target nucleic acid As used herein, “target nucleic acid,” “target RNA,” “target RNA transcript” and “nucleic acid target” each refer to a nucleic acid capable of being targeted by compounds described herein.
- target region means a portion of a target nucleic acid to which one or more compounds is targeted or is capable of hybridizing.
- target segment means the sequence of nucleotides of a target nucleic acid to which a compound is targeted.
- treat refers to administering a compound or pharmaceutical composition to an animal in order to effect an alteration or improvement of a disease, disorder, or condition in the animal.
- a therapeutically effective amount refers to an amount of a pharmaceutical agent or composition that provides a therapeutic benefit to a subject.
- a therapeutically effective amount may improve a symptom of a disease.
- a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the disease, disorder, and/or condition.
- the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc.
- the effective amount of compound in a formulation to treat a disease, disorder, and/or condition may be the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of the disease, disorder, and/or condition.
- a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.
- an oligonucleotide disclosed herein is a synthetic oligonucleotide.
- a “synthetic oligonucleotide” refers to a non-naturally occurring oligonucleotide.
- a synthetic oligonucleotide in some embodiments, refers to a synthetic DNA or synthetic RNA.
- a synthetic oligonucleotide is produced through an in vitro transcription or a polymerization reaction (e.g., artificial (non- natural) chemical synthesis, solid phase nucleic acid synthesis, or another method known by one of ordinary skill in the art).
- a synthetic oligonucleotide includes a modification at one or both ends of the nucleic acid sequence in the synthetic oligonucleotide.
- the synthetic oligonucleotide is produced by nucleic acid synthesis (e.g., in vitro), chemical nucleic acid synthesis, and/or solid phase nucleic acid synthesis, or produced through other methods well known in the art.
- one or more nucleosides of the oligonucleotide include a modification.
- an oligonucleotide (e.g., a synthetic oligonucleotide) disclosed herein is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,
- nucleic acid sequence of a synthetic oligonucleotide disclosed herein is 10 to 30, 10 to 35, 10 to 40, 10 to 45, 10 to 50, 10 to 60, 10 to 70, 10 to 80, 10 to 90, 10 to 100 or more than 100 nucleosides (e.g., nucleobases) in length.
- an oligonucleotide e.g., a synthetic oligonucleotide disclosed herein is 10 to 30 nucleosides (e.g., nucleobases) in length. In some embodiments, an oligonucleotide (e.g., a synthetic oligonucleotide) disclosed herein is 15 to 22 nucleosides (e.g., nucleobases) in length. In some embodiments, the oligonucleotide (e.g., synthetic oligonucleotide) is 20 nucleosides (e.g., nucleobases) in length. In some embodiments, the oligonucleotide (e.g., synthetic oligonucleotide) is 17 nucleosides (e.g., nucleobases) in length.
- oligonucleotide it is possible to increase or decrease the length of an oligonucleotide without eliminating activity.
- Woolf et al. Proc . Natl. Acad. Sci. USA 89:7305-7309, 1992
- a series of oligonucleotides 13-25 nucleobases in length were tested for their ability to induce cleavage of a target RNA in an oocyte injection model.
- Oligonucleotides 25 nucleobases in length with 8 or 11 mismatch bases near the ends of the oligonucleotides were able to direct specific cleavage of the target RNA, albeit to a lesser extent than the oligonucleotides that contained no mismatches.
- target specific cleavage was achieved using 13 nucleobase oligonucleotides, including those with 1 or 3 mismatches.
- oligonucleotides can have any of a variety of ranges of lengths.
- oligonucleotides consist of X to Y linked nucleosides, where X represents the fewest number of nucleosides in the range and Y represents the largest number nucleosides in the range.
- X and Y are each independently selected from 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 39, 40, 41,
- oligonucleotides consist of 12 to 13, 12 to 14, 12 to 15, 12 to 16, 12 to 17, 12 to 18, 12 to 19, 12 to 20, 12 to 21, 12 to 22, 12 to 23, 12 to 24, 12 to 25, 12 to 26, 12 to 27, 12 to 28, 12 to 29, 12 to 30, 13 to 14, 13 to 15, 13 to 16, 13 to 17, 13 to 18, 13 to 19, 13 to 20, 13 to 21, 13 to 22, 13 to 23, 13 to 24, 13 to 25, 13 to 26, 13 to 27, 13 to 28, 13 to 29, 13 to 30, 14 to 15, 14 to 16, 14 to 17, 14 to 18, 14 to 19, 14 to 20, 14 to 21, 14 to 22, 14 to 23, 14 to 24, 14 to 25, 14 to 26, 14 to 27, 14 to 28, 14 to 29, 14 to 30, 15 to 16, 15 to 17, 15 to 18, 15 to 19, 15 to 20, 15 to 21, 15 to 22, 15 to 23, 15 to 24, 15 to 25, 15 to 26, 15 to 27, 15 to 28, 15 to 29, 15 to 30, 16 to 17, 16 to 18, 16 to 19, 16 to 20, 16 to 21, 12 to 22, 15 to 23, 15 to 24, 15 to 25, 15 to 26, 15 to 27, 15 to 28, 15 to 29, 15 to 30, 16 to 17, 16
- oligonucleotides (unmodified or modified oligonucleotides, e.g., synthetic oligonucleotides) disclosed herein are further described by their nucleobase sequence.
- oligonucleotides have a nucleobase sequence that is complementary to a second oligonucleotide or an identified reference nucleic acid, such as a target nucleic acid.
- a region of an oligonucleotide has a nucleobase sequence that is complementary to a second oligonucleotide or an identified reference nucleic acid, such as a target nucleic acid.
- the nucleobase sequence of a region or entire length of an oligonucleotide is at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to the second oligonucleotide or nucleic acid, such as a target nucleic acid.
- the synthetic oligonucleotide comprises or consists of a nucleic acid sequence complementary to a region (e.g. a nucleic acid sequence segment) of a CLN3 sequence (e.g., a CLN3 sequence as set forth in any one of SEQ ID NO: 1-10 and 773).
- a synthetic oligonucleotide disclosed herein comprises or consists of a nucleic acid sequence complementary to a region (e.g., a nucleic acid sequence segment) of at least 5 (e.g., at least 10, at least 11, at least 12, at least 13, at least 14, 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, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, or more) contiguous nucleotides of a CLN3 sequence (e.g., a CLN3 sequence as set forth in any one of SEQ ID NO: 1-10 and 773).
- a region e.g., a nucleic acid sequence segment
- at least 5 e.g., at least 10, at least 11, at least 12, at least 13, at least 14, 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, at least 25, at least 26, at least 27, at least 28,
- a synthetic oligonucleotide disclosed herein comprises or consists of a nucleic acid sequence complementary to a region of at least 15 contiguous nucleotides of a CLN3 sequence. In some embodiments, a synthetic oligonucleotide disclosed herein comprises or consists of a nucleic acid sequence complementary to a region of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleotides of a CLN3 sequence. In some embodiments, a synthetic oligonucleotide disclosed herein comprises or consists of a nucleic acid sequence complementary to a region of or about 20 contiguous nucleotides of a CLN3 sequence.
- the sequence of an oligonucleotide (e.g., a synthetic oligonucleotide) encompassed by the present disclosure is at least or about 45%, at least or about 50%, at least or about 55%, at least or about 60%, at least or about 65%, at least or about 70%, at least or about 75%, at least or about 80%, at least or about 85%, at least or about 90%, at least or about 95%, at least or about 96%, at least or about 97%, at least or about 98%, at least or about 99%, or about 100%, or any range or combination thereof, identical to the sequence of an oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein (e.g., any one of the oligonucleotides provided in Table 1, any one of SEQ ID NO: 11- 772).
- modifications disclosed herein are incorporated into a modified oligonucleotide.
- modified oligonucleotides are characterized by their modification motifs and overall lengths. In certain embodiments, such parameters are each independent of one another. Thus, unless otherwise indicated, each intemucleotide linkage of an oligonucleotide having a particular sugar modification motif may be modified or unmodified and may or may not follow the modification pattern of the sugar modifications. Unless otherwise indicated, all modifications are independent of nucleobase sequence.
- Populations of modified oligonucleotides in which all of the modified oligonucleotides of the population have the same molecular formula can be stereorandom populations or chirally enriched populations. All of the chiral centers of all of the modified oligonucleotides are stereorandom in a stereorandom population. In a chirally enriched population, at least one particular chiral center is not stereorandom in the modified oligonucleotides of the population.
- the modified oligonucleotides of a chirally enriched population are enriched for beta-D ribosyl sugar moieties, and all of the phosphorothioate intemucleotide linkages are stereorandom.
- the modified oligonucleotides of a chirally enriched population are enriched for both beta-D ribosyl sugar moieties and at least one particular phosphorothioate intemucleotide linkage in a particular stereochemical configuration.
- an oligonucleotide e.g., a synthetic oligonucleotide
- an effect e.g., promoting or contributing to one or more beneficial phenotype(s) for the treatment, amelioration and/or elimination of one or more characteristics, conditions, and/or symptoms associated with Batten disease, as disclosed herein).
- the oligonucleotide (e.g., synthetic oligonucleotide) is single- stranded.
- the oligonucleotide (e.g., synthetic oligonucleotide) is hybridized to a second oligonucleotide (e.g., synthetic oligonucleotide) and forms a double- stranded oligonucleotide.
- the oligonucleotide e.g., synthetic oligonucleotide
- an oligonucleotide (e.g., a synthetic oligonucleotide) disclosed herein is a single-stranded oligonucleotide.
- oligonucleotides e.g., synthetic oligonucleotides
- oligonucleotides disclosed herein comprise an oligonucleotide having a nucleobase sequence complementary to that of a target nucleic acid.
- one oligonucleotide is paired with a second oligonucleotide to form a duplex.
- Such oligonucleotide duplexes comprise a first oligonucleotide having a region complementary to a target nucleic acid and a second oligonucleotide having a region complementary to the first oligonucleotide.
- the first oligonucleotide of an oligonucleotide duplex disclosed herein comprises or consists of (1) a modified or unmodified oligonucleotide and optionally a spacer and/or a linker and (2) a second modified or unmodified oligonucleotide and optionally a spacer and/or a linker.
- Either or both oligomeric compounds of an oligomeric duplex may comprise a conjugate group.
- One or both oligonucleotides of an oligonucleotide duplex may include non-complementary overhanging nucleosides.
- Oligonucleotide modifications include, but are not limited to, for example, (a) end modifications, e.g., 5' end modifications (phosphorylation, dephosphorylation, conjugation, inverted linkages, etc.) and 3' end modifications (conjugation, DNA nucleotides, inverted linkages, etc.); (b) base modifications, e.g., replacement with modified bases, stabilizing bases, destabilizing bases, bases that base pair with an expanded repertoire of partners, and conjugated bases; (c) sugar modifications (e.g., at the 2' position or 4' position) or replacement of the sugar; as well as (d) intemucleoside linkage modifications, including modification or replacement of phosphodiester linkages.
- An oligonucleotide e.g., a synthetic oligonucleotide disclosed herein
- the oligonucleotide modification is in one or more bases and/or sugars.
- an oligonucleotide e.g., a synthetic oligonucleotide
- an oligonucleotide includes nucleic acids having backbone sugars that are covalently attached to low molecular weight organic groups other than a hydroxyl group or hydrogen at the 2' position and other than a phosphate group or hydroxyl group at the 5' position.
- a substituted or modified oligonucleotide includes a 2'- O-alkylated ribose group.
- a modified oligonucleotide includes sugars such as hexose, 2’-F hexose, 2’-amino ribose, constrained ethyl (cEt), locked nucleic acid (LNA), bridged nucleic acid (BNA), arabinose or 2'-fluoroarabinose instead of ribose.
- an oligonucleotide e.g., a synthetic oligonucleotide
- an oligonucleotide is heterogeneous in backbone composition thereby containing any possible combination of polymer units linked together such as peptide-nucleic acids (which have an amino acid backbone with nucleic acid bases).
- an oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein includes at least one LNA modification or modified nucleoside.
- An LNA modification or modified nucleoside is a modified RNA nucleoside in which the ribose moiety is modified with an additional linkage connecting the 2’ oxygen and the 4’ carbon.
- LNA modifications enhance base stacking and backbone organization, and significantly increase the hybridization properties of oligonucleotides.
- the melting temperature of oligonucleotides comprising an LNA modification(s) can be increased relative to an unmodified oligonucleotide having the same nucleic acid sequence.
- the LNA modification is, comprises or consists of (2'-0, 4'-C methylene)-adenosine. In some embodiments, the LNA modification is, comprises or consists of 5 -methyl- (2 '-O, 4'-C methylene)-cytidine. In some embodiments, the LNA modification is, comprises or consists of (2'-0, 4'-C methylene)-cytidine. In some embodiments, the LNA modification is, comprises or consists of (2'-0, 4'-C methylene)-guanosine. In some embodiments, the LNA modification is, comprises or consists of 5-methyl-(2'-0, 4'-C methylene)-uridine.
- the oligonucleotide includes two or more LNA modifications, each of which, in some embodiments, comprises, consists of, or consists essentially of an LNA modification disclosed herein.
- an oligonucleotide e.g., a synthetic oligonucleotide
- Non-limiting examples of modifications include modifications designed to increase binding to a target strand (e.g., increase melting temperature of a hybridized pair of nucleic acid molecules, such as an oligonucleotide and a target nucleic acid), to assist in identification of the oligonucleotide or an oligonucleotide- target complex, to increase cell penetration, to stabilize against nucleases and other enzymes that degrade or interfere with the structure or activity of the oligonucleotides, to provide a mode of disruption (a terminating event) once sequence-specifically bound to a target, and to improve the pharmacokinetic properties of the oligonucleotide.
- modifications designed to increase binding to a target strand e.g., increase melting temperature of a hybridized pair of nucleic acid molecules, such as an oligonucleotide and a target nucleic acid
- modifications designed to increase binding to a target strand e.g., increase melting temperature of a hybridized pair of nucle
- an oligonucleotide (e.g., a synthetic oligonucleotide) disclosed herein comprises at least one modification (e.g., a 2’-MOE modification, an LNA modification, or any other modification disclosed herein).
- the oligonucleotide comprises at least two modifications.
- the at least two modifications comprise an LNA modification and another modification disclosed herein.
- the at least two modifications comprise a 2’-MOE modification and another modification disclosed herein.
- the at least two modifications comprise a 2’-MOE modification and an LNA modification.
- the oligonucleotide comprises two, three, four, five, six, seven, eight, nine, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more than 20 modifications (e.g., 2’-MOE modification(s), LNA modification(s), and/or any other modification(s) disclosed herein).
- an oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein includes one or more 2’-O-methoxyethyl (2’-MOE) modifications.
- the oligonucleotide includes one or more LNA modifications or modified nucleosides.
- the oligonucleotide includes a 2’-MOE modification and an LNA modification.
- an oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein comprises an end modification.
- 5’- and/or 3 ’-end modifications involve incorporation or addition of non-native or non-natural components to the 5’- and/or 3 ’-end of a nucleic acid or oligonucleotide. Such modifications may improve physicochemical properties, stability, resistance to nuclease degradation, etc.
- End modifications may include the addition of amino modifiers (e.g., 5’-DMS(0)MT-amino modifier C 6 , 5’-amino modifier C3-TLA, 5’-amino modifier C12, 5’-amino modifier C 6 - TLA, 5’-amino-dT, 5’-amino modifier-5, and 3’-amino modifier C7-CPG); thiol modifiers (e.g., 5 ’-thiol-modifier C 6 S-S and 3 ’-thiol-modifier C 6 S-S); 3’-glyceryl modification; binding modifiers (e.g., 5 ’-biotin, biotin-dT, biotin-TEG, 3’-biotin-TEG-CPG, digoxigenin, and 2,4-dinitrophenol-TEG); spacers (e.g., spacer 9, spacer 12, spacer 18, spacer C3, 3’- spacer-C3-CPG); nucleoside
- an oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein comprises a base modification.
- a base modification involves replacement of a “natural” or “native” nucleobase of an oligonucleotide with a “non-natural” or “non-native” substituent, or involves chemical modification of a native nucleobase.
- Non- limiting examples of base modifications include methylation, hydroxymethylation, alkylation, methoxyethyl modifications, and substitutions with heterocyclic, stabilizing, destabilizing, promiscuous, or conjugated base moieties.
- “Natural” nucleobases include the purine bases adenine and guanine, and the pyrimidine bases thymine, cytosine and uracil. “Non-native” or “non-natural” substituents include 5-methyl-cytosine (5-Me-C), 5- hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5- propynyl (-CoC-CH3) uracil and cytosine and other alkynyl derivatives of pyrimidine bases,
- Base modifications also include replacement of the native purine or pyrimidine base with other heterocycles, such as 7-deaza- adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone, 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and O-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine.
- Base modifications can improve various oligonucleotide properties, including stability (e.g., nuclease resistance, thermostability, chemical stability, biological stability, stability in various salt conditions, etc.), target hybridization, biocompatibility (e.g., reduced hepatotoxicity, reduced nephrotoxicity, reduced immune stimulation, etc.), mismatch discrimination, water solubility, etc.
- stability e.g., nuclease resistance, thermostability, chemical stability, biological stability, stability in various salt conditions, etc.
- target hybridization e.g., target hybridization, biocompatibility (e.g., reduced hepatotoxicity, reduced nephrotoxicity, reduced immune stimulation, etc.), mismatch discrimination, water solubility, etc.
- modified oligonucleotides comprise one or more nucleoside comprising an unmodified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleosides comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleosides that do not comprise a nucleobase, referred to as an abasic nucleoside.
- modified nucleobases are selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and O-6 substituted purines.
- modified nucleobases are selected from: 2-aminopropyladenine, 5 -hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-prop yladenine , 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (-CoC-CH3) uracil, 5- propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil),
- nucleobases include tricyclic pyrimidines, such as l,3-diazaphenoxazine-2-one, l,3-diazaphenothiazine-2-one and 9-(2- aminoethoxy)-l,3-diazaphenoxazine-2-one (G-clamp).
- Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza- adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone.
- nucleobases include those disclosed in Merigan et ah, U.S. 3,687,808, those disclosed in Englisch et al. , Angewandte Chemie, International Edition, 1991, 30: 613, the contents of each of which are herein incorporated by reference in their entireties.
- an oligonucleotide e.g., synthetic oligonucleotide
- the modification is a 2’-O-methyl (2’-O-Me) modification, a 2’-O-methoxyethyl (2’-MOE or MOE) modification, a 2’-O-methoxyethoxy- 5-methyl (5-Me-MOE) modification, an LNA modification, a 5-methyl (5-Me or iMe) modification (e.g., 5-methyl-cytidine or 5-methyl-uridine), a 5-methyl LNA modification, a 7-deaza modification, or a 7-deaza-2’-O-methyl (7deazaOM) modification.
- an oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein comprises an LNA modification and a 5-methyl modification.
- an oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein comprises an LNA modification, a 5-methyl modification, and a 7-deaza modification.
- an oligonucleotide (e.g., a synthetic oligonucleotide) disclosed herein comprises an MOE modification and a 5-methyl modification.
- an oligonucleotide (e.g., a synthetic oligonucleotide) disclosed herein comprises an MOE modification, a 5-methyl modification, and a 7-deaza modification.
- each nucleoside of an oligonucleotide (e.g., a synthetic oligonucleotide) disclosed herein comprises an MOE modification.
- an oligonucleotide e.g., a synthetic oligonucleotide
- a guanosine of the 3 or more linked guanosine nucleosides e.g., an internal guanosine of the 3 or more linked guanosine nucleosides, such as the second of the 3 or more guanosine nucleosides
- 7-deaza modified e.g., 7-deaza modified.
- the oligonucleotide comprises two or more (e.g., 2, 3, 4, 5, or more) stretches of 3 or more linked guanosine nucleosides, in which case, in some embodiments, a guanosine of each of the two or more stretches of 3 or more linked guanosine nucleosides (e.g., an internal guanosine of each of the two or more stretches of 3 or more linked guanosine nucleosides, such as each second guanosine of the two or more stretches of 3 or more guanosine nucleosides) is 7-deaza modified.
- a guanosine of each of the two or more stretches of 3 or more linked guanosine nucleosides e.g., an internal guanosine of each of the two or more stretches of 3 or more linked guanosine nucleosides, such as each second guanosine of the two or more stretches of 3 or more gua
- the oligonucleotide further comprises one or more modified intemucleoside linkages, such as phosphorothioate intemucleoside linkage(s).
- the oligonucleotide may comprise one or more LNA modified nucleosides, one or more 5-Me modified nucleosides, one or more 7-deaza modified nucleosides, one or more 2’-MOE modified nucleosides and/or one or more phosphorothioate intemucleoside linkages.
- a modified nucleoside is a 2’ -O-methyl adenosine (mA), a 2’- O-methyl cytidine (mC), a 2'-O-methyl guanosine (mG), a 2'-O-methyl uridine (mU), a deoxy adenosine (A, dA), a deoxycytidine (C, dC), a deoxyguanosine (G, dG), a deoxythymidine (T, dT), a 2'-O-methoxyethoxy adenosine (moeA, 2’-MOE-A), a 2'-O- methoxyethoxy-5-methyl cytidine (5-Me-MOE-C), a 2'-O-Methoxyethoxy Guanosine (moeG, 2’-MOE-G), a 2'-O-Methoxyethoxy-5-Meth
- oligonucleotides comprise modified and/or unmodified nucleobases arranged along the oligonucleotide or region thereof in a defined pattern or motif.
- each nucleobase is modified.
- none of the nucleobases are modified.
- each purine or each pyrimidine is modified.
- each adenine is modified.
- each guanine is modified.
- some or all of the guanine nucleobases in a modified oligonucleotide are 7-deaza guanine.
- all of the guanine nucleobases are 7-deaza guanines and all of the other nucleobases of the modified oligonucleotide are unmodified nucleobases.
- each thymine is modified.
- each uracil is modified.
- each cytosine is modified.
- some or all of the cytosine nucleobases in a modified oligonucleotide are 5-methyl cytosines.
- all of the cytosine nucleobases are 5-methyl cytosines and all of the other nucleobases of the modified oligonucleotide are unmodified nucleobases.
- modified oligonucleotides comprise a block of modified nucleobases.
- the block is at the 3 ’-end of the oligonucleotide.
- the block is within 3 nucleosides of the 3 ’-end of the oligonucleotide. In certain embodiments, the block is at the 5’-end of the oligonucleotide. In certain embodiments the block is within 3 nucleosides of the 5 ’-end of the oligonucleotide.
- oligonucleotides having a gapmer motif comprise a nucleoside comprising a modified nucleobase. In certain such embodiments, one nucleoside comprising a modified nucleobase is in the central gap of an oligonucleotide having a gapmer motif.
- the sugar moiety of said nucleoside is a 2’-deoxyribosyl sugar moiety.
- the modified nucleobase is selected from: a 2- thiopyrimidine and a 5-propynepyrimidine.
- an oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein comprises a sugar modification.
- a sugar modification involves replacement of a “natural” or “native” sugar ring of a nucleoside of a nucleic acid sequence and/or oligonucleotide (e.g., a synthetic oligonucleotide) with a “non-natural” or “non- native” substituent, or involves chemical modification of a native sugar ring.
- Sugar ring substituent groups include OH; F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N- alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted C 1 to C 10 alkyl or C2 to C 1 0 alkenyl and alkynyl.
- substituent groups include C 1 to C 10 lower alkyl, substituted lower alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O- alkaryl or O-aralkyl, SH, SCH 3 , OCN, Cl, Br, CN, CF 3 , OCF 3 , SOCH 3 , S0 2 CH 3 , ONO 2 ,
- N0 2 , N 3 NH 2 , heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an oligonucleotide or a group for improving the pharmacodynamic properties of an oligonucleotide, and other substituents having similar properties.
- a sugar modification includes a 2'-O-methoxyethoxy (2'-O- CH 2 CH 2 OCH 3 , also known as 2'-O-(2-methoxyethyl) or 2'-MOE), a 2'- dimethylaminooxyethoxy (i.e., a O(CH 2 ) 2 ON(CH 3 ) 2 group, also known as 2'-DMAOE), or 2'- dimethylaminoethoxyethoxy (also known as 2 '-O-dimethyl-amino-ethoxy-ethyl or 2'- DMAEOE; i.e., 2'-O-CH 2 -O-CH 2 -N(CH 3 ) 2 ).
- a sugar modification includes an LNA modification, a 2’-O-Me modification, or a 2’-MOE modification.
- modified sugar moieties are non-bicyclic modified sugar moieties.
- modified sugar moieties are bicyclic or tricyclic sugar moieties.
- modified sugar moieties are sugar surrogates. Such sugar surrogates may comprise one or more substitutions corresponding to those of other types of modified sugar moieties.
- modified sugar moieties are non-bicyclic modified sugar moieties comprising a furanosyl ring with one or more substituent groups none of which bridge two atoms of the furanosyl ring to form a bicyclic structure.
- non bridging substituents may be at any position of the furanosyl, including but not limited to substituents at the 2’, 4’, and/or 5’ positions.
- one or more non- bridging substituent of non-bicyclic modified sugar moieties is branched.
- 2’- substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to: 2’-F, 2’-OCH 3 (“OMe” or “O-methyl”), and 2’-O(CH 2 )OCH 3 (“MOE”).
- 2’ -substituent groups are selected from among: halo, allyl, amino, azido, SH, CN, OCN, CF 3 , OCF 3 , O-C 1 -C 10 alkoxy, O- C 1 - C 10 substituted alkoxy, O-C 1 -C 10 alkyl, O-C 1 - C 10 substituted alkyl, S-alkyl, N(R m )-alkyl, O-alkenyl, S-alkenyl, N(R m )-alkenyl, O-alkynyl, S-alkynyl, N(R m )-alkynyl, O-alkylenyl-O-alkyl, alkynyl, alkaryl, aralkyl, O-alkaryl, O- aralkyl, O(CH 2 ) 2 SCH 3 , O(CH 2 )ON(R m )(R n )
- these 2’ -substituent groups can be further substituted with one or more substituent groups independently selected from among: hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (N0 2 ), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl and alkynyl.
- Examples of 4’ -substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et ah, WO 2015/106128.
- Examples of 5’-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to: 5-methyl (R or S), 5’-vinyl, and 5’-methoxy.
- non-bicyclic modified sugar moieties comprise more than one non-bridging sugar substituent, for example, 2’-F-5’-methyl sugar moieties and the modified sugar moieties and modified nucleosides described in Migawa et ah, WO 2008/101157 and Rajeev et ah, US2013/0203836.
- modified sugar moieties comprise a substituent that bridges two atoms of the furanosyl ring to form a second ring, resulting in a bicyclic sugar moiety.
- the bicyclic sugar moiety comprises a bridge between the 4’ and the 2’ furanose ring atoms.
- 4’ to 2’ bridging sugar substituents include but are not limited to: 4’-CH 2 -2’, 4’-(CH 2 ) 2 -2' 4’-(CH 2 ) 3 -2' 4’-CH 2 -O-2’ (“LNA”), 4’-CH 2 -S-2' 4’- (CH 2 ) 2 -O-2’ (“ENA”), 4’-CH(CH 3 )-O-2’ (“constrained ethyl” or “cEt”), 4’-CH 2 -O-CH 2 -2’, 4’-CH 2 -N(R)-2’, 4’-CH(CH 2 OCH 3 )-O-2' (“constrained MOE” or “cMOE”) and analogs thereof ⁇ see, e.g., Seth et ah, U.S.
- bicyclic sugar moieties and nucleosides incorporating such bicyclic sugar moieties are further defined by isomeric configuration.
- an LNA nucleoside (described herein) may be in the a-L configuration or in the b-D configuration.
- alpha-L-methyleneoxy (4’-CH 2 -O-2’) or alpha-L-LNA bicyclic nucleosides have been incorporated into oligonucleotides that showed antisense activity (Frieden et ah, Nucleic Acids Research, 2003, 21: 6365-6372).
- general descriptions of bicyclic nucleosides include both isomeric configurations.
- modified sugar moieties comprise one or more non-bridging sugar substituent and one or more bridging sugar substituent (e.g., 5 ’-substituted and 4’-2’ bridged sugars).
- modified sugar moieties are sugar surrogates.
- the oxygen atom of the sugar moiety is replaced, e.g., with a sulfur, carbon or nitrogen atom.
- such modified sugar moieties also comprise bridging and/or non-bridging substituents as described herein.
- certain sugar surrogates comprise a 4’ -sulfur atom and a substitution at the 2’-position (see, e.g., Bhat et al, U.S. 7,875,733 and Bhat et al., U.S. 7 ,939,677 , the contents of each of which are hereby incorporated by reference in their entireties) and/or the 5’ position.
- sugar surrogates comprise rings having other than 5 atoms.
- a sugar surrogate comprises a six-membered tetrahydropyran (“THP”).
- THP tetrahydropyran
- Such tetrahydropyrans may be further modified or substituted.
- Nucleosides comprising such modified tetrahydropyrans include but are not limited to hexitol nucleic acid (“HNA”), anitol nucleic acid (“ANA”), mannitol nucleic acid (“MNA”) (see, e.g., Leumann, CJ. Bioorg. &Med. Chem. 2002, 10: 841-854), fluoro HNA:
- F-HNA see e.g. Swayze et al., U.S. 8,088,904; Swayze et al., U.S. 8,440,803; Swayze et al., U.S. 8,796,437; and Swayze et al., U.S. 9,005,906; F-HNA can also be referred to as a F-THP or 3'-fluoro tetrahydropyran), and nucleosides comprising additional modified THP compounds having the formula: wherein, independently, for each of said modified THP nucleoside:
- Bx is a nucleobase moiety
- modified THP nucleosides are provided wherein q 1 , q 2 , q 3 , q 4 q 5 , q 6 , and q 7 are each H. In certain embodiments, at least one of q 1 , q 2 , q 3 , q 4 q 5 , q 6 , and q 7 is other than H. In certain embodiments, at least one of q 1 , q 2 , q 3 , q 4 q 5 , q 6 , and q 7 is methyl. In certain embodiments, modified THP nucleosides are provided wherein one of Ri and R2 is F. In certain embodiments, Ri is F and R2 is H, in certain embodiments, Ri is methoxy and R2 is H, and in certain embodiments, Ri is methoxyethoxy and R2 is H.
- sugar surrogates comprise rings having more than 5 atoms and more than one heteroatom.
- nucleosides comprising morpholino sugar moieties and their use in oligonucleotides have been reported (see, e.g., Braasch et al., Biochemistry, 2002, 41, 4503-4510 and Summerton et al., U.S. 5,698,685; Summerton et al, U.S. 5,166,315; Summerton et al, U.S. 5,185,444; and Summerton et al., U.S. 5,034,506, the contents of each of which are hereby incorporated by reference in their entireties).
- morpholino means a sugar surrogate having the following structure:
- morpholinos may be modified, for example by adding or altering various substituent groups from the above morpholino structure.
- sugar surrogates are referred to herein as “modified morpholinos.”
- sugar surrogates comprise acyclic moieties.
- nucleosides and oligonucleotides comprising such acyclic sugar surrogates include but are not limited to: peptide nucleic acid (“PNA”), acyclic butyl nucleic acid (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11: 5853-5865), and nucleosides and oligonucleotides described in Manoharan et al., WO2011/133876.
- an oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein comprises an internucleoside linkage modification.
- an intemucleoside linkage modification involves replacement of a “natural” or “native” intemucleoside linkage of a nucleic acid molecule (e.g., an oligonucleotide) with a “non- natural” or “non-native” substituent, or involves chemical modification of a native intemucleoside linkage.
- an intemucleoside linkage modification may comprise replacement of an oxygen of the phosphate group in a 3’,5’-phosphodiester bond with a substituent atom or a substituent group, or may comprise replacement of the 3 ’,5’- phosphodiester bond or both the 3’,5’-phosphodiester bond and the sugar moiety to facilitate linkage of one nucleobase of a nucleic acid molecule to the next.
- Non-limiting examples of modified intemucleoside linkages include phosphorothioate, phosphorodithioate, N3’ phosphoramidate, boranophosphate, 2’,5’-phosphodiester, phosphonoacetate (PACE), methylphosphonate, morpholino, amide, and peptide nucleic acid linkages.
- an intemucleoside linkage modification comprised in an oligonucleotide (e.g., a synthetic oligonucleotide) disclosed herein is a phosphorothioate intemucleoside linkage modification.
- an oligonucleotide (e.g., a synthetic oligonucleotide) disclosed herein comprises a modified backbone.
- the modified backbone comprises modified intemucleoside linkages.
- the modified backbone comprises one or more phosphorothioate intemucleoside linkages.
- all of the intemucleoside linkages of the oligonucleotide are phosphorothioate intemucleoside linkages.
- modified intemucleoside linkages e.g., linkages within a modified backbone
- intemucleoside linkages that are formed by short chain alkyl or cycloalkyl intemucleoside linkages, mixed heteroatoms and alkyl or cycloalkyl intemucleoside linkages, or one or more short chain heteroatomic or heterocyclic intemucleoside linkages.
- morpholino linkages formed in part from the sugar portion of a nucleoside
- siloxane backbones sulfide, sulfoxide and sulfone backbones
- formacetyl and thioformacetyl backbones methylene formacetyl and thioformacetyl backbones
- alkene containing backbones sulfamate backbones
- sulfonate and sulfonamide backbones amide backbones; and others having mixed N, O, S and Cth component parts.
- Non-limiting examples of modified intemucleoside linkages include phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3'-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3'-5' linkages, 2'-5' linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'.
- Various salts, mixed salts and free acid forms are also included.
- nucleosides of modified oligonucleotides may be linked together using any internucleotide/internucleoside linkage.
- the two main classes of intemucleotide linking groups are defined by the presence or absence of a phosphorus atom.
- Modified intemucleotide linkages compared to naturally occurring phosphate linkages, can be used to alter, typically increase, nuclease resistance of the oligonucleotide.
- intemucleotide linkages having a chiral atom can be prepared as a racemic mixture, or as separate enantiomers. Methods of preparation of phosphorous- containing and non-phosphorous-containing intemucleotide linkages are well-known to those skilled in the art.
- Representative intemucleotide linkages having a chiral center include but are not limited to alkylphosphonates and phosphorothioates.
- Modified oligonucleotides comprising intemucleotide linkages having a chiral center can be prepared as populations of modified oligonucleotides comprising stereorandom intemucleotide linkages, or as populations of modified oligonucleotides comprising phosphorothioate linkages in particular stereochemical configurations.
- populations of modified oligonucleotides comprise phosphorothioate intemucleotide linkages wherein all of the phosphorothioate intemucleotide linkages are stereorandom.
- modified oligonucleotides can be generated using synthetic methods that result in random selection of the stereochemical configuration of each phosphorothioate linkage. Nonetheless, as is well understood by those of skill in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereochemical configuration.
- populations of modified oligonucleotides are enriched for modified oligonucleotides comprising one or more particular phosphorothioate intemucleotide linkages in a particular, independently selected stereochemical configuration.
- the particular configuration of the particular phosphorothioate linkage is present in at least 65% of the molecules in the population.
- the particular configuration of the particular phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 99% of the molecules in the population.
- Such chirally enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art, e.g., methods described in Oka et ah, JACS 125, 8307 (2003), Wan et al. Nuc. Add. Res. 42, 13456 (2014), and WO 2017/015555, the contents of each of which are herein incorporated by reference in their entireties.
- a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one indicated phosphorothioate in the (Sp) configuration.
- a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration.
- modified oligonucleotides comprising (Rp) and/or (Sp) phosphorothioates comprise one or more of the following formulas, respectively, wherein “B” indicates a nucleobase:
- chiral internucleotide linkages of modified oligonucleotides described herein can be stereorandom or in a particular stereochemical configuration.
- Further neutral intemucleotide linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides.
- Further neutral internucleotide linkages include nonionic linkages comprising mixed N, O, S and CFh component parts.
- oligonucleotides comprise modified and/or unmodified intemucleotide linkages arranged along the oligonucleotide or region thereof in a defined pattern or motif.
- each intemucleotide linkage of a modified oligonucleotide is independently selected from a phosphorothioate intemucleotide linkage and phosphodiester intemucleotide linkage.
- the sugar motif of a modified oligonucleotide is a gapmer and the intemucleotide linkages within the gap are all modified.
- some or all of the intemucleotide linkages in the wings are unmodified phosphodiester intemucleotide linkages.
- the terminal intemucleotide linkages are modified.
- the sugar motif of a modified oligonucleotide is a gapmer
- the intemucleotide linkage motif comprises at least one phosphodiester intemucleotide linkage in at least one wing, wherein the at least one phosphodiester linkage is not a terminal intemucleotide linkage, and the remaining intemucleotide linkages are phosphorothioate intemucleotide linkages.
- each phosphorothioate intemucleotide linkage is independently selected from a stereorandom phosphorothioate, a (Sp) phosphorothioate, and a (Rp) phosphorothioate.
- all of the phosphorothioate linkages are stereorandom.
- all of the phosphorothioate linkages in the wings are (Sp) phosphorothioates, and the gap comprises at least one Sp-Sp-Rp motif.
- populations of modified oligonucleotides are enriched for modified oligonucleotides comprising such intemucleotide linkage motifs.
- Substituted sugar moieties include, but are not limited to one of the following at the 2' position: H (deoxyribose); OH (ribose); F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; or O-alkyl- O-alkyl, wherein the alkyl, alkenyl and alkynyl can be substituted or unsubstituted Cl to CIO alkyl or C2 to CIO alkenyl and alkynyl.
- an oligonucleotide (e.g., a synthetic oligonucleotide) disclosed herein includes, for example, at least one nucleotide or nucleoside modified at the 2' position of the sugar.
- the nucleoside modification is a 2'-O-alkyl, 2'-O-alkyl-O- alkyl or 2'-fluoro-modified nucleotide or an end cap.
- nucleoside modifications include 2'-fluoro, 2'-amino and 2' O-methyl modifications on the ribose of pyrimidines, abasic residues or an inverted base at the 3' end of the oligonucleotide.
- an oligonucleotide includes a single modified nucleoside. In some embodiments, an oligonucleotide includes at least two modified nucleosides, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, at least 20 or more nucleosides, up to the entire length of the oligonucleotide (e.g., synthetic oligonucleotide). In some embodiments, each nucleoside of the oligonucleotide is a modified nucleoside.
- Nucleosides or nucleobases include the natural purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U).
- Modified nucleosides include other synthetic and natural nucleobases such as inosine, xanthine, hypoxanthine, nubularine, isoguanisine, tubercidine, 2-(halo)adenine, 2-(alkyl)adenine, 2-(propyl)adenine, 2-(amino)adenine, 2-(aminoalkyll)adenine, 2-(aminopropyl)adenine, 2-(methylthio) N6- (isopentenyl)adenine, 6-(alkyl)adenine, 6-(methyl)adenine, 7-(deaza)adenine, 8- (alkenyl)adenine, 8-(alkyl)adenine, 8-
- modified oligonucleotides comprise one or more modified nucleosides comprising a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more modified intemucleotide linkages. In such embodiments, the modified, unmodified, and differently modified sugar moieties, nucleobases, and/or intemucleotide linkages of a modified oligonucleotide define a pattern or motif. In certain embodiments, the patterns of sugar moieties, nucleobases, and intemucleotide linkages are each independent of one another.
- a modified oligonucleotide may be described by its sugar motif, nucleobase motif and/or intemucleotide linkage motif (as used herein, nucleobase motif describes the modifications to the nucleobases independent of the sequence of nucleobases).
- an oligonucleotide (e.g., a synthetic oligonucleotide) disclosed herein is a chimeric oligonucleotide.
- Chimeric oligonucleotides may be formed as composite structures of two or more oligonucleotides, modified oligonucleotides, and/or oligonucleotide mimetics. Such compounds have also been referred to in the art as hybrids or mixed backbone or chimeric or gapmers.
- a gapmer is an oligonucleotide that has at least three discrete portions, two of which are similar e.g., include one or more common backbone modifications or include one or more common nucleoside modifications, and surround a region that is distinct, e.g., does not include the common backbone modifications or does not include the common nucleoside modifications.
- the oligonucleotide has a gap segment. In some embodiments, the oligonucleotide does not have a gap segment. In some embodiments, the oligonucleotide comprises or consists of a 5 ’-wing segment, a 3 ’-wing segment, and a gap segment.
- a “5 ’-wing segment” corresponds to two or more linked nucleosides positioned at the 5 ’-end of an oligonucleotide (e.g., a synthetic oligonucleotide) and corresponding to nucleosides positioned before the first nucleoside at the 5 ’-end of a gap segment.
- a “3 ’-wing segment” corresponds to two or more linked nucleosides positioned after the last nucleic acid at the 3’ end of the gap segment and including the last nucleic acid at the 3’ end of the oligonucleotide.
- at least one nucleoside of the 5 ’-wing segment and/or at least one nucleoside of the 3 ’-wing segment comprises a modification.
- oligonucleotides comprise one or more type of modified sugar and/or unmodified sugar moiety arranged along the oligonucleotide or region thereof in a defined pattern or sugar motif.
- sugar motifs include but are not limited to any of the sugar modifications discussed herein.
- modified oligonucleotides comprise or consist of a region having a gapmer motif, which is defined by two external regions or “wings” and a central or internal region or “gap.”
- the three regions of a gapmer motif (the 5’-wing, the gap, and the 3 ’-wing) form a contiguous sequence of nucleosides wherein at least some of the sugar moieties of the nucleosides of each of the wings differ from at least some of the sugar moieties of the nucleosides of the gap.
- the sugar moieties of the nucleosides of each wing that are closest to the gap differ from the sugar moiety of the neighboring gap nucleosides, thus defining the boundary between the wings and the gap (i.e., the wing/gap junction).
- the sugar moieties within the gap are the same as one another.
- the gap includes one or more nucleoside having a sugar moiety that differs from the sugar moiety of one or more other nucleosides of the gap.
- the sugar motifs of the two wings are the same as one another (symmetric gapmer).
- the sugar motif of the 5’-wing differs from the sugar motif of the 3’-wing (asymmetric gapmer).
- a “gap segment” corresponds to two or more linked nucleosides in an oligonucleotide, which are positioned between the 5 ’-wing segment and the 3 ’-wing segment.
- a gap segment refers to one or more linked nucleosides located at the center or near the center of an oligonucleotide, such as a synthetic oligonucleotide.
- the gap segment consists of two to three, two to four, two to five, two to six, two to seven, two to eight, two to nine, two to 10, two to 20, two to 30, two to 40, two to 50, three to four, three to five, three to six, three to seven, three to eight, three to nine, three to 10, three to 20, three to 30, three to 40, three to 50, four to five, four to six, four to seven, four to eight, four to nine, four to 10, four to 20, four to 30, four to 40, four to 50, five to six, five to seven, five to eight, five to nine, five to 10, five to 20, five to 30, five to 40, five to 50, six to seven, six to eight, six to nine, six to 10, six to 20, six to 30, six to 40, six to 50, seven to eight, seven to nine, seven to 10, seven to 20, seven to 30, seven to 40, seven to 50, eight to nine, eight to 10, eight to 20, eight to 30, eight to 40, eight to 50, 10 to 20, 10 to 30, 10 to 40, 10 to 50, 10 to 30,
- the wings of a gapmer comprise 1-5 nucleosides.
- each nucleoside of each wing of a gapmer comprises a modified sugar moiety.
- at least one nucleoside of each wing of a gapmer comprises a modified sugar moiety.
- at least two nucleosides of each wing of a gapmer comprises a modified sugar moiety.
- at least three nucleosides of each wing of a gapmer comprises a modified sugar moiety.
- at least four nucleosides of each wing of a gapmer comprises a modified sugar moiety.
- the gap of a gapmer comprises 7-12 nucleosides.
- each nucleoside of the gap of a gapmer comprises a 2’-P-D-deoxyribosyl sugar moiety.
- at least one nucleoside of the gap of a gapmer comprises a modified sugar moiety.
- the gapmer is a deoxy gapmer.
- the nucleosides on the gap side of each wing/gap junction comprise 2’-deoxyribosyl sugar moieties and the nucleosides on the wing sides of each wing/gap junction comprise modified sugar moieties.
- each nucleoside of the gap comprises a 2 ? -b- ⁇ - deoxyribosyl sugar moiety.
- each nucleoside of each wing of a gapmer comprises a modified sugar moiety.
- modified oligonucleotides comprise or consist of a region having a fully modified sugar motif.
- each nucleoside of the fully modified region of the modified oligonucleotide comprises a modified sugar moiety.
- each nucleoside of the entire modified oligonucleotide comprises a modified sugar moiety.
- modified oligonucleotides comprise or consist of a region having a fully modified sugar motif, wherein each nucleoside within the fully modified region comprises the same modified sugar moiety, referred to herein as a uniformly modified sugar motif.
- a fully modified oligonucleotide is a uniformly modified oligonucleotide.
- each nucleoside of a uniformly modified oligonucleotide comprises the same 2’-modification. In some embodiments, each nucleoside of an oligonucleotide disclosed herein comprises a 2’-MOE modification.
- the lengths (number of nucleosides) of the three regions of a gapmer may be provided using the notation [number of nucleosides in the 5 ’-wing] - [number of nucleosides in the gap] - [number of nucleosides in the 3’-wing].
- a 3-10-3 gapmer consists of 3 linked nucleosides in each wing and 10 linked nucleosides in the gap. Where such nomenclature is followed by a specific modification, that modification is the modification in each sugar moiety of each wing and the gap nucleosides comprise 2 ’ - b- D-dco x yri bo s y 1 sugar moieties.
- a 5-10-5 MOE gapmer consists of 5 linked 2’-MOE nucleosides in the 5’- wing, 10 linked 2’ ⁇ -D-deoxynucleosides in the gap, and 5 linked 2’ -MOE nucleosides in the 3’-wing.
- a 3-10-3 LNA gapmer consists of 3 linked LNA nucleosides in the 5’-wing, 10 linked 2’-P-D-deoxynucleosides in the gap, and 3 linked LNA nucleosides in the 3 ’-wing.
- modified oligonucleotides are 5-10-5 MOE gapmers. In certain embodiments, modified oligonucleotides are 3-10-3 BNA gapmers. In certain embodiments, modified oligonucleotides are 3-10-3 LNA gapmers. In certain embodiments, modified oligonucleotides are 3-10-3 cEt gapmers.
- the gap segment comprises a nucleoside having a 2’-O-Me modification. In some embodiments, the gap segment comprises two to 10 (i.e., 2, 3, 4, 5, 6,
- the gap segment does not comprise a nucleoside having a 2’-O-Me modification.
- the gap segment comprises a phosphorothioate internucleoside linkage.
- the gap segment comprises two to 10 (i.e., 2, 3, 4, 5, 6, 7, 8, 9, or 10) phosphorothioate internucleoside linkages.
- the gap segment comprises all phosphorothioate intemucleoside linkages (i.e., each internucleoside linkage within the gap segment is a phosphorothioate intemucleoside linkage).
- the gap segment does not comprise phosphorothioate intemucleoside linkages.
- the gap segment comprises a phosphodiester intemucleoside linkage. In some embodiments, the gap segment comprises two to 10 phosphodiester intemucleoside linkages. In some embodiments, the gap segment comprises all phosphodiester intemucleoside linkages (i.e., each intemucleoside linkage within the gap segment is a phosphodiester intemucleoside linkage). In some embodiments, the gap segment does not comprise phosphodiester intemucleoside linkages.
- the modification is a 2’-O-Me modification.
- the nucleosides in the synthetic oligonucleotide are modified with one or more other modifications disclosed herein.
- the intemucleoside linkages within the gap segment and the linkages connecting the gap segment to the 3 ’-wing segment and/or the 5’-wing segment are all phosphorothioate linkages (*).
- the intemucleoside linkages connecting the rest of the nucleosides of both the 5’ and 3 ’-wing segments are phosphodiester linkages.
- the intemucleoside linkages connecting the rest of the nucleosides of both the 5’ and 3 ’-wing segments are phosphorothioate linkages (*). In some embodiments, all intemucleoside linkages connecting the nucleosides of the 5 ’-wing segment, the gap segment, and the 3 ’-wing segment are phosphorothioate linkages (*).
- an oligonucleotide (e.g., a synthetic oligonucleotide) disclosed herein comprises a fully-phosphorothioate backbone (i.e., each intemucleoside linkage of the oligonucleotide is a phosphorothioate internucleoside linkage), and each nucleoside of the oligonucleotide comprises an MOE modification.
- one or more guanosine nucleosides is 7-deaza modified.
- the oligonucleotide comprises a fully-phosphorothioate backbone
- each nucleoside of the oligonucleotide comprises an MOE modification
- one or more guanosine nucleosides of the oligonucleotide is 7-deaza modified
- one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or each) cytosine nucleoside of the oligonucleotide is 5-methyl modified.
- an oligonucleotide e.g., a synthetic oligonucleotide
- a nucleic acid e.g. a region of a CLN3 sequence, such as a CLN3 sequence as set forth in any one of SEQ ID NO: 1-10 and 773
- hybridization can occur in an antiparallel configuration between the oligonucleotide and the nucleic acid.
- a double-stranded nucleic acid or oligonucleotide can be “complementary” or “sufficiently complementary” to another nucleic acid or oligonucleotide if hybridization can occur between one of the strands of the first nucleic acid or oligonucleotide and the second nucleic acid or oligonucleotide.
- Complementarity e.g., the degree to which one polynucleotide is complementary with another
- An oligonucleotide (e.g., a synthetic oligonucleotide) may be complementary to or sufficiently complementary to a region of a nucleic acid even if the two base sequences are not 100% complementary, as long as the duplex structure formed between has the desired stability.
- two nucleic acids are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences are able to form base pairing interactions (e.g., Watson-Crick base pairing interactions) between at least or about 45%, at least or about 50%, at least or about 55%, at least or about 60%, at least or about 65%, at least or about 70%, at least or about 75%, at least or about 80%, at least or about 85%, at least or about 90%, at least or about 95%, at least or about 96%, at least or about 97%, at least or about 98%, at least or about 99%, or about 100% of their nucleotides, or any range or combination thereof.
- base pairing interactions e.g., Watson-Crick base pairing interactions
- two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions (e.g., Watson-Crick base pairing interactions) between at least or about 45% of their nucleotides.
- base pairing interactions e.g., Watson-Crick base pairing interactions
- two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 50% of their nucleotides.
- two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 55% of their nucleotides.
- two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 60% of their nucleotides.
- two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 65% of their nucleotides.
- two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 70% of their nucleotides.
- two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 75% of their nucleotides.
- two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 80% of their nucleotides.
- two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 85% of their nucleotides.
- two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 90% of their nucleotides.
- two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 92.5% of their nucleotides.
- two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 95% of their nucleotides. In some embodiments, two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 96% of their nucleotides.
- two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 97% of their nucleotides.
- two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 98% of their nucleotides.
- two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 99% of their nucleotides.
- two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 100% of their nucleotides.
- two nucleic acid sequences that are each 20 nucleosides in length are considered 80% complementary if 16 of their respective 20 nucleosides are able to form base-pairing interactions.
- Two nucleic acid sequences that are of different lengths may also be complementary.
- a nucleic acid sequence that is 20 nucleosides in length may be complementary to or sufficiently complementary to a nucleic acid sequence that is longer if their sequences are able to form base pairing interactions (e.g., Watson-Crick base pairing interactions) between a sufficient number of nucleotides of the 20 nucleoside length nucleic acid sequence and a sufficient number of nucleotides of the longer nucleic acid sequence.
- a nucleic acid sequence that is 20 nucleosides in length is considered 100% complementary to a longer nucleic acid sequence if all 20 of its nucleosides are able to form base-pairing interactions with 20 contiguous nucleosides of the longer nucleic acid sequence.
- a nucleic acid sequence that is 20 nucleosides in length is considered 80% complementary to or sufficiently complementary to a longer nucleic acid sequence if 16 of its 20 nucleosides are able to form base-pairing interactions with 16 nucleosides of the longer nucleic acid sequence in a complementary sequence alignment.
- oligonucleotides are complementary to the target nucleic acid over the entire length of the oligonucleotide. In certain embodiments, oligonucleotides are 99%, 95%, 90%, 85%, or 80% complementary to the target nucleic acid. In certain embodiments, oligonucleotides are at least 80% complementary to the target nucleic acid over the entire length of the oligonucleotide and comprise a region that is 100% or fully complementary to a target nucleic acid. In certain embodiments, the region of full complementarity is from 6 to 20, 10 to 18, or 18 to 20 nucleobases in length.
- oligonucleotides comprise one or more mismatched nucleobases relative to the target nucleic acid.
- antisense activity against the target is reduced by such mismatch, but activity against a non-target is reduced by a greater amount.
- selectivity of the oligonucleotide for its target is improved by the presence of a mismatch.
- an oligonucleotide e.g., a synthetic oligonucleotide
- an oligonucleotide (e.g., a synthetic oligonucleotide) comprises a mismatch at position 1, 2, 3, 4, 5, 6, 7, or 8 from its 3’-end.
- the mismatch is specifically positioned within an oligonucleotide having a gapmer motif.
- the mismatch is at position 1, 2, 3, 4, 5, 6, 7, or 8 from the 5’-end of the gap region.
- the mismatch is at position 9, 8, 7, 6, 5, 4, 3, 2, 1 from the 3 ’-end of the gap region.
- the mismatch is at position 1, 2, 3, or 4 from the 5 ’-end of the wing region.
- the mismatch is at position 4, 3, 2, or 1 from the 3 ’-end of the wing region.
- oligomeric compounds comprise or consist of an oligonucleotide (e.g., a synthetic oligonucleotide disclosed herein) comprising a region that is complementary to a target nucleic acid.
- the target nucleic acid is an endogenous RNA molecule.
- the target nucleic acid encodes a protein.
- the target nucleic acid is a mature mRNA or a pre- mRNA.
- the target nucleic acid includes intronic, exonic and/or untranslated regions.
- the target RNA is a mature mRNA.
- the target nucleic acid is a pre-mRNA.
- the target region is entirely within an intron. In certain embodiments, the target region spans an intron/exon junction (i.e., is partially within an intron and partially within an exon). In certain embodiments, the target region is at least 50% within an intron.
- the target nucleic acid is the RNA transcriptional product of a retrogene. In certain embodiments, the target nucleic acid is a non-coding RNA. In certain such embodiments, the target non- coding RNA is selected from: a long non-coding RNA (IncRNA), a short non-coding RNA, and an intronic RNA molecule.
- oligomeric compounds comprise or consist of an oligonucleotide (e.g., a synthetic oligonucleotide disclosed herein) comprising a region that is complementary to a target nucleic acid.
- the target nucleic acid is a CLN3 nucleic acid.
- contacting a cell with an oligomeric compound comprising a nucleic acid sequence with complementarity to any one of SEQ ID NO: 1-10 and 773 reduces the amount of CLN3 RNA in the cell or reduces the amount of a particular CLN3 RNA isoform in the cell, and in certain embodiments modulates (e.g., reduces or increases) the amount of CLN3 protein or the amount of a particular CLN3 isoform in the cell.
- the oligomeric compound consists of a modified oligonucleotide (e.g., a synthetic oligonucleotide disclosed herein).
- contacting a cell with an oligomeric compound comprising a nucleic acid sequence with complementarity to any one of SEQ ID NO: 1-10 and 773 results in amelioration of symptoms of a disease or disorder (e.g., an NCL disease, such as CLN3 Batten disease).
- a disease or disorder e.g., an NCL disease, such as CLN3 Batten disease.
- the oligomeric compound comprises or consists of a modified oligonucleotide (e.g., a synthetic oligonucleotide disclosed herein).
- the oligomeric compound comprises or consists of a modified oligonucleotide, at least one spacer moiety, and at least one linker moiety.
- an oligonucleotide e.g., a synthetic oligonucleotide
- a region of a CLN3 sequence e.g., a human CLN3 sequence, such as a CLN3 sequence provided in any one of SEQ ID NO: 1- 10.
- exon 14 (nucleotides 19426-19566 of SEQ ID NO: 1 and nucleotides 14426-14566 of SEQ ID NO: 2); intron 14 (nucleotides 19567-19667 of SEQ ID NO: 1 and nucleotides 14567-14667 of SEQ ID NO: 2); or exon 15 (nucleotides 19668-20024 of SEQ ID NO: 1 and nucleotides 14668-15024 of SEQ ID NO: 2) of CLN3.
- an oligonucleotide e.g., a synthetic oligonucleotide
- a region of a murine CLN3 sequence e.g., a murine CLN3 sequence provided in SEQ ID NO: 773.
- the region is within intron 4 of CLN3. In some embodiments, the region is within exon 5 of CLN3. In some embodiments, the region is within intron 5 of CLN3. In some embodiments, the region is within exon 6 of CLN3. In some embodiments, the region is within intron 6 of CLN3. In some embodiments, the region is within intron 8 of CLN3. In some embodiments, the region is within exon 9 of CLN3. In some embodiments, the region is within intron 9 of CLN3.
- the region overlaps a portion of an intron and a portion of an exon.
- the region is partially within intron 4 and partially within exon 5; partially within exon 5 and partially within intron 5; partially within intron 5 and partially within exon 6; partially within exon 6 and partially within intron 6; partially within intron 8 and partially within exon 9; or partially within exon 9 and partially within intron 9.
- the region is between nucleotides 9,462 and 9,947 of SEQ ID NO: 1 (nucleotides 5462-5947 of SEQ ID NO: 2) or between nucleotides 13,185 and 13,397 of SEQ ID NO: 1 (nucleotides 8185-8397 of SEQ ID NO: 2).
- SNAs Spherical nucleic acids
- a “spherical nucleic acid” refers to a three-dimensional arrangement of nucleic acids or oligonucleotides, such as synthetic oligonucleotides, forming an oligonucleotide shell, with oligonucleotides arranged radially around and/or on the exterior of a core (e.g., a nanoparticle core).
- the core is a hollow core produced by a three-dimensional arrangement of molecules which form the outer boundary of the core.
- the molecules may be in the form of a lipid layer (e.g. lipid monolayer or lipid bilayer), which has a hollow center.
- the molecules may be in the form of lipids, such as amphipathic lipids (e.g., sterols), which are linked to or associated with, either directly or indirectly, an end of the oligonucleotide (e.g., synthetic oligonucleotide).
- amphipathic lipids e.g., sterols
- tocopherols or sterols, such as cholesterol linked (e.g., indirectly attached) to an end of an oligonucleotide (e.g., a synthetic oligonucleotide) may associate with the outer surface of a core (e.g., a hollow core), such that the oligonucleotides radiate outward from the core.
- an SNA comprises an oligonucleotide shell comprising a synthetic oligonucleotide and a core.
- a synthetic oligonucleotide is associated with the core (e.g., a nanoparticle core) through a covalent or non-covalent interaction.
- a synthetic oligonucleotide is associated with the exterior surface of the core.
- the synthetic oligonucleotides are associated with the core (e.g., exterior surface) through a molecular species via, for instance, a hydrophobic interaction.
- the synthetic oligonucleotide is associated with a molecular species (e.g., a hydrophobic group), either directly or indirectly. In some embodiments, the synthetic oligonucleotide is indirectly associated with or indirectly attached to a molecular species (e.g., hydrophobic group) through a spacer. In some embodiments, the molecular species (e.g., hydrophobic group) is associated with the core. In some embodiments, the core is a liposome core. In some embodiments, the liposome core comprises a lipid bilayer. In some embodiments, the synthetic oligonucleotide is covalently attached to one or more lipids of the lipid layer. In some embodiments, the synthetic oligonucleotide is not covalently attached to one or more lipids of the lipid layer. In some embodiments, the synthetic oligonucleotide is covalently attached to a molecular species.
- a molecular species e.g., a
- an SNA disclosed herein comprises a single population of synthetic oligonucleotides (i.e., each synthetic oligonucleotide of the oligonucleotide shell is the same, having the same sequence).
- an SNA disclosed herein may comprise two populations, three populations, four populations, five populations, six populations, seven populations, eight populations, nine populations, 10 populations, or more of distinct synthetic oligonucleotides (i.e., the synthetic oligonucleotides of the oligonucleotide shell represent two, three, four, etc. different synthetic oligonucleotides having different sequences).
- an SNA disclosed herein comprises a synthetic oligonucleotide comprising a molecular species indirectly attached to a nucleotide of the synthetic oligonucleotide.
- the molecular species is linked to the core of the SNA.
- the molecular species is indirectly attached to the nucleotide at the 3 ’-end of the synthetic oligonucleotide, such that the 3 ’-end of the synthetic oligonucleotide is linked to the core of the SNA and the 5 ’-end of the synthetic oligonucleotide is distal from the core (e.g., is oriented away from the core).
- the molecular species is indirectly attached to the nucleotide at the 5 ’-end of the synthetic oligonucleotide, such that the 5 ’-end of the synthetic oligonucleotide is linked to the core of the SNA and the 3 ’-end of the synthetic oligonucleotide is distal from the core (e.g., is oriented away from the core).
- an SNA disclosed herein comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence and a second synthetic oligonucleotide comprising a second nucleic acid sequence.
- the oligonucleotide(s) of an SNA disclosed herein are indirectly attached to a molecular species.
- a first molecular species is indirectly attached to a nucleotide of a first synthetic oligonucleotide and a second molecular species is indirectly attached to a nucleotide of a second synthetic oligonucleotide.
- the first molecular species is indirectly attached to the nucleotide at the 3 ’-end of the first synthetic oligonucleotide and the second molecular species is indirectly attached to the nucleotide at the 5 ’-end of the second synthetic oligonucleotide. In some embodiments, the first molecular species is indirectly attached to the nucleotide at the 5 ’-end of the first synthetic oligonucleotide and the second molecular species is indirectly attached to the nucleotide at the 3 ’-end of the second synthetic oligonucleotide.
- the first molecular species is indirectly attached to the nucleotide at the 5 ’-end of the first synthetic oligonucleotide and the second molecular species is indirectly attached to the nucleotide at the 5 ’-end of the second synthetic oligonucleotide. In some embodiments, the first molecular species is indirectly attached to the nucleotide at the 3 ’-end of the first synthetic oligonucleotide and the second molecular species is indirectly attached to the nucleotide at the 3 ’-end of the second synthetic oligonucleotide.
- an SNA comprises additional synthetic oligonucleotides (e.g., a third synthetic oligonucleotide comprising a third nucleic acid sequence, a fourth synthetic oligonucleotide comprising a fourth nucleic acid sequence, etc.), each of which is indirectly attached via a nucleotide at its 3’ - or 5 ’-end to a molecular species.
- the end of each synthetic oligonucleotide to which the molecular species is attached is linked to the core of the SNA and the opposite end of the synthetic oligonucleotide is distal from the core (e.g., is oriented away from the core).
- conjugation means two entities stably bound to one another by any physiochemical means. It is important that the nature of the attachment is such that it does not impair substantially the effectiveness of either entity. Keeping these parameters in mind, any covalent or non-covalent linkage known to those of ordinary skill in the art may be employed. In some embodiments, covalent linkage is preferred.
- Noncovalent conjugation includes hydrophobic interactions, ionic interactions, high affinity interactions such as biotin avidin and biotin streptavidin complexation and other affinity interactions. Such means and methods of attachment are well known to those of ordinary skill in the art.
- an SNA comprises an oligonucleotide shell.
- an oligonucleotide shell includes one or more oligonucleotides (e.g., synthetic oligonucleotides) on and/or around the exterior of the core.
- the oligonucleotide shell comprises or consists of one, two, three, four, five, six, seven, eight, nine, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 1500, about 2000, about 3000, about 4000, about 5000, about 10,000, about 15,000, about 20,000 or more synthetic oligonucleotides, or any range or combination thereof.
- the oligonucleotide shell comprises or consists of 2-1000, 2-900, 2-800, 2-700, 2-600, 2-500, 2-400, 2-300, 2-200, 2-100, 2-90, 2-80, 2-70, 2-60, 2-50, 2-45, 2-40, 2-35, 2- 30, 2-25, 2-20, 2-15 or 2-10 oligonucleotides (e.g., synthetic oligonucleotides).
- the oligonucleotide shell comprises or consists of 5-100, 10-100, 15-100, 20- 100, 25-100, 50-100, 5-50, 10-50, 15-50, 20-50, 25-50, 5-40, 10-40, 15-40, 20-40, 25-40, 5- 30, 10-30, 15-30, 20-30, 25-30, 5-25, 10-25, 15-25 or 20-25 oligonucleotides (e.g., synthetic oligonucleotides).
- the oligonucleotide shell comprises or consists of 30 or about 30 oligonucleotides (e.g., synthetic oligonucleotides).
- each synthetic oligonucleotide of the oligonucleotide shell comprises the same nucleic acid sequence.
- the synthetic oligonucleotides of the oligonucleotide shell comprise different nucleic acid sequences (e.g., the synthetic oligonucleotides comprise two different sequences, three different sequences, four different sequences, five different sequences, six different sequences, seven different sequences, eight different sequences, or more).
- each different nucleic acid sequence may be comprised within an equal proportion of the synthetic oligonucleotides, such that the proportion of synthetic oligonucleotides having a particular nucleic acid sequence within a shell comprising n distinct nucleic acid sequences is 1 In (e.g., two nucleic acid sequences are each comprised within 1/2 or 50% of the synthetic oligonucleotides, three nucleic acid sequences are each comprised within 1/3 or 33% of the synthetic oligonucleotides, four nucleic acid sequences are each comprised within 1/4 or 25% of the synthetic oligonucleotides, etc.).
- each different nucleic acid sequence may be comprised within different proportions of the synthetic oligonucleotides (e.g., one nucleic acid sequence may be comprised within 75% of the synthetic oligonucleotides and a second nucleic acid sequence may be comprised within 25% of the synthetic oligonucleotides; one nucleic acid sequence may be comprised within 50% of the synthetic oligonucleotides, a second nucleic acid sequence may be comprised within 25% of the synthetic oligonucleotides and a third nucleic acid sequence may be comprised within 25% of the synthetic oligonucleotides, etc.).
- an SNA disclosed herein comprises or consists of lipids or lipid molecules and oligonucleotides (e.g., synthetic oligonucleotides) at a molar ratio between 100 to 1 and 10 to 1, between 100 to 1 and 20 to 1, between 100 to 1 and 30 to 1, between 100 to 1 and 40 to 1, between 100 to 1 and 50 to 1, between 100 to 1 and 60 to 1, between 100 to 1 and 70 to 1, between 100 to 1 and 80 to 1, between 100 to 1 and 90 to 1, between 90 to 1 and 10 to 1, between 90 to 1 and 20 to 1, between 90 to 1 and 30 to 1, between 90 to 1 and 40 to 1, between 90 to 1 and 50 to 1, between 90 to 1 and 60 to 1, between 90 to 1 and 70 to 1, between 90 to 1 and 80 to 1, between 80 to 1 and 10 to 1, between 80 to 1 and 20 to 1, between 80 to 1 and 30 to 1, between 80 to 1 and 40 to 1, between 80 to 1 and 50 to 1, between 80 to 1 and 60 to 1, between 80 to 1 and 70 to 1, between 80 to 1 and 20 to 1, between 80 to 1
- an SNA disclosed herein comprises lipids or lipid molecules and oligonucleotides (e.g., synthetic oligonucleotides) at a molar ratio of at least or about 10 to 1, 20 to 1, 30 to 1, 40 to 1, 50 to 1, 60 to 1, 70 to 1, 80 to 1, 90 to 1, or 100 to 1 of lipids to oligonucleotide (e.g., synthetic oligonucleotide), or any range or combination thereof.
- oligonucleotides e.g., synthetic oligonucleotides
- an SNA disclosed herein comprises lipids or lipid molecules and oligonucleotides (e.g., synthetic oligonucleotides) at a molar ratio of between 55 to 1 and 45 to 1 of lipid or lipid molecules to oligonucleotide. In some embodiments, an SNA disclosed herein comprises lipids or lipid molecules and oligonucleotides (e.g., synthetic oligonucleotides) at a molar ratio of or about 50 to 1 of lipid to oligonucleotide (e.g., synthetic oligonucleotide).
- the oligonucleotide portion of the lipids or lipid molecules to oligonucleotide ratio is divided between more than one population of oligonucleotides (e.g., a first population of synthetic oligonucleotides, a second population of synthetic oligonucleotides, etc.), such that the ratio represents the total number of oligonucleotides of the SNA regardless of their nucleic acid sequences.
- an SNA comprising a first population of synthetic oligonucleotides and a second population of synthetic oligonucleotides may comprise lipids or lipid molecules at a molar ratio of 50 to 0.5 to 0.5 of lipids or lipid molecules to first population of synthetic oligonucleotides to second population of synthetic oligonucleotides.
- the SNA may comprise lipids or lipid molecules at a molar ratio of 50 to 1, where the oligonucleotide portion is divided equally between the more than two populations of synthetic oligonucleotides.
- an SNA comprising a first population of synthetic oligonucleotides and a second population of synthetic oligonucleotides may comprise different amounts of the first population of synthetic oligonucleotides and the second population of synthetic oligonucleotides, such that the molar ratio of lipids or lipid molecules to the first population of synthetic oligonucleotides to the second population of synthetic oligonucleotides is, for example, 50 to 0.1 to 0.9, 50 to 0.2 to 0.8, 50 to 0.3 to 0.7,
- the SNA may comprise lipids or lipid molecules at a molar ratio of 50 to 1, where the oligonucleotide portion is divided unequally between the more than two populations of synthetic oligonucleotides (e.g., the total oligonucleotide portion sums to 1, but each individual population does not represent an equal proportion of the total).
- the oligonucleotides are on the exterior surface of the core (e.g., liposome core).
- at least one oligonucleotide e.g., a synthetic oligonucleotide
- has its 5 ’-terminus exposed on the exterior surface away from the core e.g., the 5 ’-terminus is located at the end of the oligonucleotide distal from the core.
- all of the oligonucleotides (e.g., synthetic oligonucleotides) in an SNA have their 5 ’-termini exposed on the exterior surface away from the core (e.g., the 5’-termini are located at the ends of the oligonucleotides distal from the core).
- at least one oligonucleotide e.g., a synthetic oligonucleotide
- has its 3 ’-terminus exposed on the exterior surface away from the core e.g., the 3 ’-terminus is located at the end of the oligonucleotide distal from the core.
- all of the oligonucleotides (e.g., synthetic oligonucleotides) in an SNA have their 3 ’-termini exposed on the exterior surface away from the core (e.g., the 3 ’-termini are located at the ends of the oligonucleotides distal from the core).
- the SNA does not include an oligonucleotide (e.g., a synthetic oligonucleotide) inside the core (e.g., liposome core).
- an SNA comprises a first synthetic oligonucleotide and a second synthetic oligonucleotide.
- the 5’-terminus of the first synthetic oligonucleotide is exposed on the exterior surface of the SNA away from the core
- the 3’- terminus of the second synthetic oligonucleotide is exposed on the surface of the SNA away from the core.
- the 3 ’-terminus of the first synthetic oligonucleotide is exposed on the exterior surface of the SNA away from the core
- the 5 ’-terminus of the second synthetic oligonucleotide is exposed on the surface of the SNA away from the core.
- the 3 ’-terminus of the first synthetic oligonucleotide is exposed on the exterior surface of the SNA away from the core, and the 3 ’-terminus of the second synthetic oligonucleotide is exposed on the surface of the SNA away from the core.
- the 5 ’-terminus of the first synthetic oligonucleotide is exposed on the exterior surface of the SNA away from the core, and the 5 ’-terminus of the second synthetic oligonucleotide is exposed on the surface of the SNA away from the core.
- two or more of the oligonucleotides (e.g., synthetic oligonucleotides) in an SNA are crosslinked to one another. In some embodiments, all of the oligonucleotides (e.g., synthetic oligonucleotides) in an SNA are crosslinked to one or more additional oligonucleotides. In some embodiments, the oligonucleotides (e.g., synthetic oligonucleotides) in an SNA are not crosslinked.
- an SNA disclosed herein has a diameter of, or a population or plurality of SNAs disclosed herein has a mean diameter of about 10 to about 150 nm.
- the mean diameter of the population of SNAs is from or about 15 nm to about 100 nm, about 20 nm to about 100 nm, about 25 nm to about 100 nm, about 15 nm to about 50 nm, about 20 nm to about 50 nm, about 10 nm to about 70 nm, about 15 nm to about 70 nm about 20 nm to about 70 nm, about 10 nm to about 30 nm, about 15 nm to about 30 nm, about 20 nm to about 30 nm, about 10 nm to about 40 nm, about 15 nm to about 40 nm, about 20 nm to about 40 nm, about 10 nm to about 80 nm, about 15 nm to about 80 nm,
- the mean diameter of the population of SNAs is from about 15 nm to about 45 nm.
- an SNA disclosed herein has a diameter, or a population of SNAs disclosed herein has a mean diameter of or about 10 nm, about 15 nm, about 20 nm, about 30 nm, about 40 nm, about 50 nm, about 60 nm, about 70 nm, about 80 nm, about 90 nm, or about 100 nm.
- an SNA disclosed herein has a diameter, or a population or a plurality of SNAs disclosed herein have a mean diameter of 30 nm or about 30 nm.
- the SNAs disclosed herein may be stable self-assembling nanostructures.
- the SNA may comprise an oligonucleotide (e.g., a synthetic oligonucleotide) of 18- 21 nucleosides in length having a sequence disclosed herein, wherein a hydrophobic group at the 3’ or 5’ terminus of the oligonucleotide self-associates to form the core or associates with the core of the nanostructure in water or other suitable solvents.
- an oligonucleotide e.g., a synthetic oligonucleotide of 18- 21 nucleosides in length having a sequence disclosed herein, wherein a hydrophobic group at the 3’ or 5’ terminus of the oligonucleotide self-associates to form the core or associates with the core of the nanostructure in water or other suitable solvents.
- a hydrophobic group as used herein may include cholesterol, a cholesteryl or modified cholesteryl residue, adamantine, dihydrotesterone, long chain alkyl, long chain alkenyl, long chain alkynyl, olely-lithocholic, cholenic, oleoyl-cholenic, palmityl, heptadecyl, myrisityl, bile acids, cholic acid or taurocholic acid, deoxycholate, oleyl litocholic acid, oleoyl cholenic acid, glycolipids, phospholipids, sphingolipids, isoprenoids, such as steroids, vitamins, such as vitamin E, fatty acids either saturated or unsaturated, fatty acid esters, such as triglycerides, pyrenes, porphyrines, Texaphyrine, adamantane, acridines, biotin, coumarin, fluorescein, rhodamine
- an oligonucleotide described herein is attached to the external surface of a core to form a corona or shell of oligonucleotides.
- an oligonucleotide described herein is comprised in a spherical nucleic acid (SNA).
- SNA spherical nucleic acid
- the core is a liposome, an inorganic nanoparticle, a self-organizing oligonucleotide-based structure, a dendrimer, or a protein.
- the nanoparticle core of an SNA disclosed herein is a solid core or a hollow core.
- a solid core is a spherical- shaped material with or without a hollow center.
- a “spherical shape” refers to a general shape and does not imply or is not limited to a perfect sphere or round shape. In some embodiments, a spherical shape includes imperfections.
- the core comprises or consists of a metal core (e.g., any metal). Non-limiting examples of metals include gold, silver, platinum, aluminum, palladium, copper, cobalt, indium, nickel and mixtures thereof.
- the core comprises gold or is a gold core. In some embodiments, the core can be a lattice structure including degradable gold.
- the core may comprise semiconductor and/or magnetic materials.
- Solid cores can be constructed from a wide variety of materials known to those skilled in the art including but not limited to: noble metals (gold, silver), transition metals (iron, cobalt) and metal oxides (silica).
- a solid core may be inert, paramagnetic, or superparamagnetic.
- the solid cores can be constructed from either pure compositions of described materials, or in combinations of mixtures of any number of materials, or in layered compositions of materials.
- a solid core can be composed of a polymeric core such as amphiphilic block copolymers, hydrophobic polymers such as polystyrene, poly(lactic acid), poly(lactic co-glycolic acid), poly(glycolic acid), poly(caprolactone) and other biocompatible polymers known to those skilled in the art.
- the core comprises or consists of a solid core or a semi-solid core.
- the core of an SNA disclosed herein is a hollow core.
- a hollow core has at least some space in the center region of a shell material.
- a hollow core is a liposome core.
- a liposome core as used herein refers to a centrally located core compartment formed by a component of the lipids or phospholipids that form a lipid bilayer. “Liposomes” are artificial, self-closed vesicular structures of various sizes and shapes, where one or several membranes encapsulate an aqueous core.
- liposome membranes are formed from lipid bilayer membranes, where the hydrophilic head groups are oriented towards aqueous environments, and the lipid chains are oriented away from aqueous environments.
- Liposomes can be formed as well from other amphiphilic monomeric and polymeric molecules, such as polymers, like block copolymers, or polypeptides.
- Unilamellar vesicles are liposomes defined by a single membrane enclosing an aqueous space.
- oligo- or multilamellar vesicles are built up of several membranes.
- the membranes are roughly 4 nm thick and are composed of amphiphilic lipids, such as phospholipids, of natural or synthetic origin.
- the membrane properties can be modified by the incorporation of other lipids such as sterols or cholic acid derivatives.
- the lipid bilayer is composed of two layers of lipids or lipid molecules. Each lipid or lipid molecule in a layer is oriented substantially parallel to adjacent lipids or lipid molecules, and two layers of lipids or lipid molecules that form a bilayer have the polar ends of their molecules exposed to the aqueous phase and the non-polar ends adjacent to each other. The two lipid layers that form the lipid bilayer are substantially parallel to one another.
- the central aqueous region of the liposomal core may be empty or filled fully or partially with water, an aqueous emulsion, oligonucleotides, or other therapeutic or diagnostic agents or aqueous solutions thereof.
- a lipid bilayer or liposome core can be constructed from one or more lipids known to those in the art including but not limited to: l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dimyristoyl-sn-phosphatidylcholine (DMPC), l-palmitoyl-2-oleoyl-sn- phosphatidylcholine (POPC), l,2-distearoyl-sn-glycero-3-phospho-(l'-rac-glycerol) (DSPG), l,2-dioleoyl-sn-glycero-3-phospho-(l'-rac-glycerol) (DOPG), l,2-distearoyl-sn-glycero-3- phosphocholine (DSPC), l,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), l,2-di-(9Z
- lipid refers to its conventional sense as a generic term encompassing fats, lipids, and alcohol-ether-soluble constituents of protoplasm, which are insoluble in or immiscible with water.
- Lipids usually consist of a hydrophilic and a hydrophobic moiety. In water, lipids can self-organize to form bilayer membranes, where the hydrophilic moieties (head groups) are oriented towards the aqueous phase, and the lipophilic moieties (acyl chains) are embedded in the hydrophobic region between the two hydrophilic layers comprised within the bilayer. Lipids can also comprise two hydrophilic moieties (bola amphiphiles).
- membranes may be formed from a single lipid layer, and not a bilayer.
- lipids are fats, fatty oils, essential oils, waxes, steroids, sterols, phospholipids, glycolipids, sulpholipids, aminolipids, chromolipids, and fatty acids.
- the term encompasses both naturally occurring and synthetic lipids.
- the lipids are steroids, sterols (e.g., cholesterol), phospholipids, including phosphatidyl, phosphatidylcholines and phosphatidylethanolamines and sphingomyelins.
- sterols e.g., cholesterol
- phospholipids including phosphatidyl, phosphatidylcholines and phosphatidylethanolamines and sphingomyelins.
- fatty acids could be about 12-24 carbon chains in length, containing up to 6 double bonds.
- the fatty acids are linked to a backbone, which may be derived from glycerol.
- the fatty acids within one lipid can be different (asymmetric), or there may be only 1 type of fatty acid chain present, e.g. lysolecithins.
- non-cationic lipids are derived from natural sources, such as lecithins (phosphatidylcholines) purified from egg yolk, bovine heart, brain, liver or soybean.
- the SNA includes a neutral lipid.
- the neutral lipid may be, for example, l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dimyristoyl-sn- phosphatidylcholine (DMPC), l-palmitoyl-2-oleoyl-sn-phosphatidylcholine (POPC), 1,2- distearoyl-sn-glycero-3-phospho-(l'-rac-glycerol) (DSPG), l,2-dioleoyl-sn-glycero-3- phospho-(l'-rac-glycerol) (DOPG), l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2- dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), l,2-di-(9Z-octadecenoyl)-sn-glycero-3- phosphoethanolamine (
- the core is a niosome core.
- a noisome is a vesicle formed from non-ionic surfactant oriented in a bilayer.
- Niosomes commonly have cholesterol added as an excipient, but other lipid-based and non-lipid-based constituents can also be included. Methods for preparation of niosomes are known in the art.
- polyethylene glycol (PEG) is included during or following niosome preparation.
- Niosome vesicles are structurally and functionally analogous to liposomes, but are based on non-ionic surfactant rather than lipid as the primary constituent.
- Common non-ionic surfactants used include sorbitans (spans) or polysorbates (tween); however, a wide variety of non-ionic surfactants can be used to prepare niosomes.
- the core comprises or consists of a protein.
- the protein is an antibody, a glycoprotein, an enzyme, a receptor, a repeat containing protein, or an engineered alternative scaffold.
- the core is a protein selected from any of asialoglycoprotein, albumin, fibronectin, transferrin, alpha- galactosidase, b-glucosidase, b-cerebrosidase, a-glucosidase, a-mannosidase, b- glucuronidase, b-hexosamininidase A, acid lipase, lipase, hydrogenase, protease, oxygenase, non-naturally occurring alternative scaffold proteins such as a Centyrin (see Diem et al, Protein Engineering, Design and Selection , 2014, page 419-419; Dudkin et al, WO 2019/118818), a DARPin (see Stum
- nanostructures can be made entirely of oligonucleotides.
- the core is a self-assembled three-dimensional structure made entirely from oligonucleotides.
- the core is a dendrimer made from oligonucleotides (see Getts et al, WO 2017/143171, Kadushin et al, WO 2010/017544, Getts et al, WO 2016/168578, Nilsen et al, US 5,484,904, Nilsen et al, US 6,274,723).
- the core is a dendrimer made from materials other than oligonucleotides.
- the core comprises dendrimers comprising poly(amidoamine) (PAMAM).
- PAMAM poly(amidoamine)
- the dendrimer-branched polymer may consist of PAMAM, polyester, polyether, poly-lysine, or polyethylene glycol (PEG), polypeptide dendrimers.
- the core (e.g., liposome core) of an SNA disclosed herein has a diameter of, or the cores (e.g., liposome cores) of a population of SNAs disclosed herein has a mean diameter of about 10 to about 150 nm.
- the diameter of the core or the mean diameter of the population of cores is from about 15 nm to about 100 nm, about 20 nm to about 100 nm, about 25 nm to about 100 nm, about 15 nm to about 50 nm, about 20 nm to about 50 nm, about 10 nm to about 70 nm, about 15 nm to about 70 nm, about 20 nm to about 70 nm, about 10 nm to about 30 nm, about 15 nm to about 30 nm, about 20 nm to about 30 nm, about 10 nm to about 40 nm, about 15 nm to about 40 nm, about 20 nm to about 40 nm, about 10 nm to about 80 nm, about 15 nm to about 80 nm, or about 20 nm to about 80 nm.
- the core (e.g., liposome core) of an SNA disclosed herein has a diameter of, or the cores (e.g., liposome cores) of a population of SNAs disclosed herein has a mean diameter of about 15 nm to about 45 nm.
- the core (e.g., liposome core) of an SNA disclosed herein has a diameter of, or the cores (e.g., liposome cores) of a population of SNAs disclosed herein has a mean diameter of about 10 nm, about 15 nm, about 20 nm, about 30 nm, about 40 nm, about 50 nm, about 60 nm, about 70 nm, about 80 nm, about 90 nm, or about 100 nm.
- the core (e.g., liposome core) of an SNA disclosed herein has a diameter of, or the cores (e.g., liposome cores) of a population of SNAs disclosed herein has a mean diameter of about 30 nm.
- the core (e.g., liposome core) of an SNA disclosed herein has a diameter, or the cores (e.g., liposome cores) of a population of SNAs disclosed herein has a mean diameter of about or less than about 10 nm, 15 nm, 20 nm, 25 nm, 30 nm, 35 nm, and/or 40 nm, or any range or combination thereof.
- the core (e.g., liposome core) of an SNA disclosed herein has a diameter, or the cores (e.g., liposome cores) of a population of SNAs disclosed herein has a mean diameter of about or less than 40 nm.
- the core (e.g., liposome core) of an SNA disclosed herein has a diameter
- the cores (e.g., liposome cores) of a population of SNAs disclosed herein has a mean diameter of or about 20 nm.
- oligomeric compounds which consist of an oligonucleotide (modified or unmodified) and optionally one or more spacers and/or linkers.
- spacers comprise or consist of one or more moiety which connects the linker moiety to the oligonucleotide.
- a linker moiety may be attached to either or both ends of an oligonucleotide (e.g., a synthetic oligonucleotide) disclosed herein, or a linker moiety may be attached to an intermediate position of an oligonucleotide.
- linker moieties attached to either or both ends of an oligonucleotide are terminal groups.
- the linker is attached at the 3’ and/or 5’-end of the oligonucleotide. In some embodiments, the linker is attached at or near the 3 ’-end of the oligonucleotide. In certain embodiments, the linker is attached at or near the 5 ’-end of the oligonucleotide.
- a synthetic oligonucleotide comprises a molecular species.
- the molecular species anchors the synthetic oligonucleotide to the core (e.g., liposome core) of an SNA disclosed herein.
- the molecular species is a linker.
- a molecular species may be attached at various positions of a synthetic oligonucleotide (e.g., at the 3 ’-end or 5 ’-end of a nucleotide sequence of a synthetic oligonucleotide disclosed herein).
- a molecular species is attached to the nucleotide at the 3 ’-end of a synthetic oligonucleotide disclosed herein. In some embodiments, a molecular species is attached to the nucleotide at the 5 ’-end of a synthetic oligonucleotide disclosed herein.
- a molecular species is attached to a nucleotide not at a terminus of a synthetic oligonucleotide disclosed herein (e.g., an internal nucleotide one, two, three, four, five, six, seven, eight, nine, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more positions away from the 3’- or 5’-end).
- a synthetic oligonucleotide disclosed herein e.g., an internal nucleotide one, two, three, four, five, six, seven, eight, nine, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more positions away from the 3’- or 5’-end.
- the molecular species enhances the stability of the synthetic oligonucleotide against 3’ - or 5 ’-exonucleases.
- a molecular species is attached to or associated with an internal nucleotide or a nucleotide on a branch of a synthetic oligonucleotide.
- a molecular species is attached to a 2’-position of a nucleoside of a synthetic oligonucleotide.
- a molecular species is linked to the heterocyclic base of a nucleoside of a synthetic oligonucleotide.
- the molecular species is modified.
- the molecular species comprises multiple moieties.
- the molecular species is, comprises or consists of a lipophilic (i.e., hydrophobic) moiety.
- the molecular species is, comprises or consists of a lipophilic (i.e., hydrophobic) moiety and a hydrophilic moiety.
- the molecular species comprises multiple lipophilic (i.e., hydrophobic) moieties and/or multiple hydrophilic moieties.
- the molecular species is, comprises or consists of a hydrophobic moiety, such as a cholesterol or a cholesteryl ester.
- the molecular species is, comprises or consists of a cholesterol and an additional moiety. In some embodiments, the molecular species is, comprises or consists of a cholesterol and a hydrophilic moiety. In some embodiments, the molecular species comprises a cholesterol and a triethylene glycol (TEG). In some embodiments, the molecular species comprises one or more cholesterols and one or more TEGs. In some embodiments, the molecular species comprises or consists of a cholesterol linked (e.g., covalently linked) to a TEG. In some embodiments, the molecular species is a cholesteryl ester.
- TEG triethylene glycol
- the molecular species is a cholesteryl ester linked (e.g., covalently linked) to a TEG.
- the molecular species is, comprises or consists of N-cholesteryl-3-aminopropyl-triethyleneglycol-glyceryl- 1-O-phosphodiester (3CholTEG).
- the molecular species is a lipid, a sterol, lipid moieties such as a cholesterol moiety, cholic acid, a thioether (e.g., hexyl- S-tritylthiol), a thiocholesterol, an aliphatic chain (e.g., dodecandiol or undecyl residues), a phospholipid (e.g., di-hexadecyl- rac-glycerol or triethylammonium l,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate), a polyamine or a polyethylene glycol chain, or adamantane acetic acid, a palmityl moiety, an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety, stearyl, C 1 6 alkyl chain, bile acids,
- oligonucleotides e.g., synthetic oligonucleotides
- the molecular species is selected from tocopherols, sphingolipids such as sphingosine, sphingosine phosphate, methylated sphingosines and sphinganines, ceramides, ceramide phosphates, 1-0 acyl ceramides, dihydroceramides, 2-hydroxy ceramides, sphingomyelin, glycosylated sphingolipids, sulfatides, gangliosides, phosphosphingolipids, and phytosphingosines of various lengths and saturation states and their derivatives, phospholipids such as phosphatidylcholines, lysophosphatidylcholines, phosphatidic acids, lysophosphatidic acids, cyclic LPA
- a molecular species is connected to an oligonucleotide (e.g., a synthetic oligonucleotide) disclosed herein through a spacer (e.g., a non-nucleotidic spacer).
- a spacer e.g., a non-nucleotidic spacer
- Non-limiting examples of spacers include abasic residues (dSpacer), oligoethyleneglycol, such as triethyleneglycol (spacer 9 or iSp9; TEG) or hexaethylenegylcol (spacer 18 or iSp 18; HEG), alkane-diol (e.g., butanediol), C 22 alkyl, C 20 alkyl, C1 ⁇ 2 alkyl, C 10 alkyl, C 21 alkyl, C 19 alkyl, C 18 alkyl, C 1 5 alkyl, Cu alkyl, C 1 3 alkyl, C 1 2 alkyl, C 1 1 alkyl, C 9 alkyl, C 8 alkyl, C 7 alkyl, Ce alkyl, C 5 alkyl, C 22 alkenyl, C 20 alkenyl, C ⁇ e alkenyl, C 10 alkenyl, C 21 alkenyl, C 19 alkenyl, C 1 s alkenyl
- the synthetic oligonucleotide is attached to the spacer through a covalent bond (e.g., phosphodiester, phosphorodithioate or phosphorothioate bond).
- the spacer does not comprise or consist of an oligonucleotide spacer. The spacer in some embodiments appears just once in the molecule or in some embodiments is incorporated several times (e.g., via phosphodiester, phosphorothioate, methylphosphonate, or amide linkages).
- the individual spacer moieties may be attached to one another and/or to the synthetic oligonucleotide via phosphodiester, phosphorothioate, methylphosphonate, or amide linkages.
- the spacer comprises a TEG and/or a HEG.
- the spacer comprises or consists of hexa(ethyleneglycol)phosphodiester- hexa(ethyleneglycol)phosphodiester (HEG-HEG).
- the molecular species connected to the spacer comprises or consists of hexa(ethyleneglycol)phosphodiester- hexa(ethyleneglycol)phosphodiester-3-O-(N-cholesteryl-3-aminopropyl)-triethyleneglycol- glyceryl- 1-O-phosphodiester (HEG-HEG-CholTEG or CholTEG-HEG-HEG) .
- the HEG- HEG-CholTEG or CholTEG-HEG-HEG may be connected (e.g., directly or indirectly) to the 5’-end and/or the 3’-end of a nucleic acid or oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein.
- a nucleic acid or oligonucleotide e.g., synthetic oligonucleotide
- the spacer comprises or consists of the structure
- the molecular comprises or consists of the structure
- the molecular species connected to the spacer comprises or consists of the structure
- a synthetic oligonucleotide disclosed herein comprises, consists essentially of, or consists of the structure
- the oligonucleotide in Formula IV has the nucleic acid sequence of an Antisense Sequence listed in Table 1.
- a synthetic oligonucleotide comprising, consisting essentially of, or consisting of the structure of Formula IV has the structure of an ASO Structure listed in Table 1.
- the spacer and/or the linker it is desirable for the spacer and/or the linker to be cleaved from the oligonucleotide.
- oligonucleotide compounds comprising a particular spacer and/or linker are better taken up by a particular cell type, but once the compounds have been taken up, it is desirable that the spacer and/or linker be cleaved to release the oligonucleotide.
- certain spacers and linkers may comprise one or more cleavable moieties.
- a cleavable moiety is a cleavable bond.
- a cleavable moiety is a group of atoms comprising at least one cleavable bond. In certain embodiments, a cleavable moiety comprises a group of atoms having one, two, three, four, or more than four cleavable bonds. In certain embodiments, a cleavable moiety is selectively cleaved inside a cell or subcellular compartment, such as a lysosome. In certain embodiments, a cleavable moiety is selectively cleaved by endogenous enzymes, such as nucleases.
- a cleavable bond is selected from an amide, an ester, an ether, one or both esters of a phosphodiester, a phosphate ester, a carbamate, or a disulfide bond. In certain embodiments, a cleavable bond is one or both of the esters of a phosphodiester. In certain embodiments, a cleavable moiety comprises a phosphate or phosphodiester. In certain embodiments, the cleavable moiety is a phosphate linkage between an oligonucleotide and a spacer moiety or a linker moiety.
- a cleavable moiety comprises or consists of one or more nucleosides.
- the one or more nucleosides are linked to one another and/or to the remainder of the oligonucleotide through cleavable bonds.
- such cleavable bonds are unmodified phosphodiester bonds.
- a cleavable moiety is 2'-deoxynucleoside that is attached to either the 3' or 5'- terminal nucleoside of an oligonucleotide by a phosphate internucleotide linkage and covalently attached to the remainder of the spacer or linker moiety by a phosphate or phosphorothioate linkage.
- the cleavable moiety is 2'- deoxy adenosine.
- administration of an oligonucleotide e.g., synthetic oligonucleotide
- an SNA e.g., SNA
- a composition thereof e.g., pharmaceutical composition thereof
- administration of an oligonucleotide to a subject increases the amount of a particular splicing isoform of CLN3 in a cell or subject.
- the level is increased in the cell or subject by at least or about 5%, at least or about 10%, at least or about 15%, at least or about 16%, at least or about 17%, at least or about 18%, at least or about 19%, at least or about 20%, at least or about 21%, at least or about 22%, at least or about 23%, at least or about 24%, at least or about 25%, at least or about 26%, at least or about 27%, at least or about 28%, at least or about 29%, at least or about 30%, at least or about 31%, at least or about 32%, at least or about 33%, at least or about 34%, at least or about 35%, at least or about 36%, at least or about 37%, at least or about 38%, at least or about 39%, at least or about 40%, at least or about 41%, at least or about 42%, at least or about 43%, at least or about 44%, at least or about 45%, at least or about 46%, at least or about 47%, at least or about 40%
- an oligonucleotide e.g., synthetic oligonucleotide
- a SNA a SNA
- a composition thereof e.g., pharmaceutical composition thereof
- the level in the cell is increased by at least or about 5%, at least or about 10%, at least or about 15%, at least or about 16%, at least or about 17%, at least or about 18%, at least or about 19%, at least or about 20%, at least or about 21%, at least or about 22%, at least or about 23%, at least or about 24%, at least or about 25%, at least or about 26%, at least or about 27%, at least or about 28%, at least or about 29%, at least or about 30%, at least or about 31%, at least or about 32%, at least or about 33%, at least or about 34%, at least or about 35%, at least or about 36%, at least or about 37%, at least or about 38%, at least or about 39%, at least or about 40%, at least or about 41%, at least or about 42%, at least or about 43%, at least or about 44%, at least or about 45%, at least or about 46%, at least or about 47%, at least or about
- an oligonucleotide e.g., synthetic oligonucleotide
- a SNA a SNA
- a composition thereof e.g., pharmaceutical composition thereof
- the CLN3 splicing isoform levels are increased in a cell or cells of a subject with a disease or disorder (e.g., Batten disease). In some embodiments, the CLN3 splicing isoform levels are increased in a tissue or tissues of a subject with a disease or disorder (e.g., Batten disease). In some embodiments, the CLN3 splicing isoform levels are increased in an organ or organs of a subject with a disease or disorder (e.g., Batten disease).
- the CLN3 splicing isoform levels are increased in the nervous system of a subject with a disease or disorder (e.g., Batten disease). In some embodiments, the CLN3 splicing isoform levels are increased in the eye of a subject with a disease or disorder (e.g. Batten disease). In some embodiments, the CLN3 splicing isoform levels are increased in the cortex, cerebellum, hippocampus, midbrain, thalamus, and/or occipital lobe of a subject with a disease or disorder (e.g., Batten disease).
- a disease or disorder e.g., Batten disease
- the CLN3 splicing isoform levels are increased in the cortex, cerebellum, hippocampus, midbrain, thalamus, and/or occipital lobe of a subject with a disease or disorder (e.g., Batten disease).
- the CLN3 splicing isoform levels are increased in a neuron, a microglial cell, and/or an astrocyte of a subject with a disease or disorder (e.g., Batten disease). In some embodiments, the CLN3 splicing isoform levels are increased in a cell of the eye (e.g., a retinal cell) of a subject with a disease or disorder (e.g., Batten disease).
- administration of an oligonucleotide (e.g., synthetic oligonucleotide), an SNA, or a composition thereof (e.g., pharmaceutical composition thereof) to a subject decreases the amount of a particular splicing isoform of CLN3 in a cell or subject.
- the level is decreased in the cell or subject by at least or about 5%, at least or about 10%, at least or about 15%, at least or about 16%, at least or about 17%, at least or about 18%, at least or about 19%, at least or about 20%, at least or about
- an oligonucleotide e.g., synthetic oligonucleotide
- a SNA a SNA
- a composition thereof e.g., pharmaceutical composition thereof
- the level in the cell is decreased by at least or about 5%, at least or about 10%, at least or about 15%, at least or about 16%, at least or about 17%, at least or about 18%, at least or about 19%, at least or about 20%, at least or about 21%, at least or about 22%, at least or about 23%, at least or about 24%, at least or about 25%, at least or about 26%, at least or about 27%, at least or about 28%, at least or about 29%, at least or about 30%, at least or about 31%, at least or about 32%, at least or about 33%, at least or about 34%, at least or about 35%, at least or about 36%, at least or about 37%, at least or about 38%, at least or about 39%, at least or about 40%, at least or about 41%, at least or about 42%, at least or about 43%, at least or about 44%, at least or about 45%, at least or about 46%, at least or about 47%, at least or about
- an oligonucleotide e.g., synthetic oligonucleotide
- a SNA a composition thereof
- a dose which results in a decreased amount of a particular splicing isoform of CLN3 in the subject by at least or about 5%, at least or about 10%, at least or about 15%, at least or about 16%, at least or about 17%, at least or about 18%, at least or about 19%, at least or about 20%, at least or about 21%, at least or about 22%, at least or about 23%, at least or about 24%, at least or about 25%, at least or about 26%, at least or about 27%, at least or about 28%, at least or about 29%, at least or about 30%, at least or about 31%, at least or about 32%, at least or about 33%, at least or about 34%, at least or about 35%, at least or about 36%, at least or about 37%
- the CLN3 splicing isoform levels are decreased in a cell or cells of a subject with a disease or disorder (e.g., Batten disease). In some embodiments, the CLN3 splicing isoform levels are decreased in a tissue or tissues of a subject with a disease or disorder (e.g., Batten disease). In some embodiments, the CLN3 splicing isoform levels are decreased in an organ or organs of a subject with a disease or disorder (e.g., Batten disease). In some embodiments, the CLN3 splicing isoform levels are decreased in the nervous system of a subject with a disease or disorder (e.g., Batten disease).
- a disease or disorder e.g., Batten disease
- the CLN3 splicing isoform levels are decreased in the eye of a subject with a disease or disorder (e.g. Batten disease). In some embodiments, the CLN3 splicing isoform levels are decreased in the cortex, cerebellum, hippocampus, midbrain, thalamus, and/or occipital lobe of a subject with a disease or disorder (e.g., Batten disease). In some embodiments, the CLN3 splicing isoform levels are decreased in a neuron, a microglial cell, and/or an astrocyte of a subject with a disease or disorder (e.g., Batten disease). In some embodiments, the CLN3 splicing isoform levels are decreased in a cell of the eye (e.g., a retinal cell) of a subject with a disease or disorder (e.g., Batten disease).
- a cell of the eye e.g., a retinal cell
- administering increases the ratio of one CLN3 splicing isoform (e.g., a CLN3 mRNA splicing isoform) to another.
- CLN3 splicing isoform lacking exons 5, 7 and 8 is increased relative to a CLN3 splicing isoform lacking only exons 7 and 8, or not lacking exon 5.
- a CLN3 splicing isoform lacking exons 6, 7 and 8 is increased relative to a CLN3 splicing isoform lacking only exons 7 and 8, or not lacking exon 6.
- a CLN3 splicing isoform lacking exons 7, 8 and 9 is increased relative to a CLN3 splicing isoform lacking only exons 7 and 8, or not lacking exon 9.
- one CLN3 splicing isoform e.g., a CLN3 splicing isoform lacking exons 5, 7 and 8; a CLN3 splicing isoform lacking exons 6, 7 and 8; or a CLN3 splicing isoform lacking exons 7, 8 and 9) is increased relative to another CLN3 splicing isoform (e.g.,.
- a CLN3 splicing isoform lacking exons 7 and 8) such that the shorter isoform (e.g., lacking three exons) is 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9- fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13- fold, 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, 20-fold or more higher than the longer isoform (e.g., lacking two exons).
- an oligonucleotide e.g., synthetic oligonucleotide
- an SNA e.g., SNA
- a composition thereof e.g., pharmaceutical composition thereof
- administration of an oligonucleotide e.g., synthetic oligonucleotide
- an SNA e.g., SNA
- a composition thereof e.g., pharmaceutical composition thereof
- the level is increased in the cell or subject by at least or about 5%, at least or about 10%, at least or about 15%, at least or about 16%, at least or about 17%, at least or about 18%, at least or about 19%, at least or about 20%, at least or about 21%, at least or about 22%, at least or about 23%, at least or about 24%, at least or about 25%, at least or about 26%, at least or about 27%, at least or about 28%, at least or about 29%, at least or about 30%, at least or about 31%, at least or about 32%, at least or about 33%, at least or about 34%, at least or about 35%, at least or about 36%, at least or about 37%, at least or about 38%, at least or about 39%, at least or about 40%, at least or about 41%, at least or about 42%, at least or about 43%, at least or about 44%, at least or about 45%, at least or about 46%, at least or about 47%, at least or about 40%
- an oligonucleotide e.g., synthetic oligonucleotide
- a SNA a cell to increase the amount of CLN3 protein in the cell.
- a composition thereof e.g., pharmaceutical composition thereof
- the level in the cell is increased by at least or about 5%, at least or about 10%, at least or about 15%, at least or about 16%, at least or about 17%, at least or about 18%, at least or about 19%, at least or about 20%, at least or about 21%, at least or about 22%, at least or about 23%, at least or about 24%, at least or about 25%, at least or about 26%, at least or about 27%, at least or about 28%, at least or about 29%, at least or about 30%, at least or about 31%, at least or about 32%, at least or about 33%, at least or about 34%, at least or about 35%, at least or about 36%, at least or about 37%, at least or about 38%, at least or about 39%, at least or about 40%, at least or about 41%, at least or about 42%, at least or about 43%, at least or about 44%, at least or about 45%, at least or about 46%, at least or about 47%, at least or about
- an oligonucleotide e.g., synthetic oligonucleotide
- a SNA a SNA
- a composition thereof e.g., pharmaceutical composition thereof
- the CLN3 protein levels are increased in a cell or cells of a subject with a disease or disorder (e.g., Batten disease). In some embodiments, the CLN3 protein levels are increased in a tissue or tissues of a subject with a disease or disorder (e.g., Batten disease). In some embodiments, the CLN3 protein levels are increased in an organ or organs of a subject with a disease or disorder (e.g., Batten disease). In some embodiments, the CLN3 protein levels are increased in the nervous system of a subject with a disease or disorder (e.g., Batten disease). In some embodiments, the CLN3 protein levels are increased in the eye of a subject with a disease or disorder (e.g. Batten disease).
- a disease or disorder e.g. Batten disease
- the CLN3 protein levels are increased in the cortex, cerebellum, hippocampus, midbrain, thalamus, and/or occipital lobe of a subject with a disease or disorder (e.g., Batten disease). In some embodiments, the CLN3 protein levels are increased in a neuron, a microglial cell, and/or an astrocyte of a subject with a disease or disorder (e.g., Batten disease). In some embodiments, the CLN3 protein levels are increased in a cell of the eye (e.g., a retinal cell) of a subject with a disease or disorder (e.g., Batten disease).
- a cell of the eye e.g., a retinal cell
- the level of a CLN3 nucleic acid can be measured according to methods known in the art.
- measuring the level of a CLN3 nucleic acid may refer to using laboratory methods known to those of ordinary skill in the art to quantify or qualitatively evaluate the amount of CLN3 RNA (e.g., CLN3 pre-mRNA and/or CLN3 mRNA) in a given sample, using methods including but not limited to quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), Northern blotting, in situ hybridization, or spectrophotometric analysis.
- qRT-PCR quantitative real-time reverse transcription polymerase chain reaction
- the level of a CLN3 protein, including a particular splicing isoform of a CLN3 protein, can be measured according to methods known in the art.
- measuring CLN3 protein levels may refer to using laboratory methods known to those of ordinary skill in the art to quantify or qualitatively evaluate the amount of CLN3 protein in a given sample, using methods including but not limited to Western blotting, enzyme-linked immunosorbent assays (ELISA), immunohistochemical staining, immunofluorescent staining, mass spectrometry, spectrophotometric analysis, or colorimetric analysis such as bicinchinonic acid (BCA) assays.
- ELISA enzyme-linked immunosorbent assays
- immunohistochemical staining immunofluorescent staining
- mass spectrometry mass spectrometry
- spectrophotometric analysis or colorimetric analysis such as bicinchinonic acid (BCA) assays.
- BCA bicinchinonic acid
- a “reference level,” refers to a corresponding level in a subject with a disease or disorder (e.g., a subject with Batten disease) who has been administered a linear oligonucleotide (e.g., a synthetic oligonucleotide disclosed herein) which is not in an SNA format or pharmaceutical composition thereof; to a corresponding level in a subject with a disease or disorder (e.g., Batten disease) who has not been administered an SNA (e.g., an SNA disclosed herein) or pharmaceutical composition thereof; to a corresponding level in a subject with a disease or disorder (e.g., Batten disease) who has not been administered a linear oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein; to a corresponding level in a subject with the disease or disorder (e.g., Batten disease) prior to administration of an oligonucleotide (e.g., synthetic oligon
- a value that is less than” and equivalent phrases refer to values which are decreased or quantified to be smaller than a value or values to which they are compared (e.g., a reference value or reference values).
- a value that is greater than” and equivalent phrases refer to values which are increased or quantified to be larger than a value or values to which they are compared (e.g., a reference value or reference values).
- a disease or disorder refers to a disease or disorder in a subject.
- the disease or disorder is a neurodegenerative disease or disorder.
- the disease or disorder is associated with or caused by genetic mutations, such as in the gene CLN3.
- the disease or disorder is associated with mutations in the CLN3 gene causing production of an abnormally short protein, which may be broken down or may interfere with normal cellular processes.
- the disease or disorder is associated with the accumulation of proteins and other cellular products in lysosomes, which may occur in cells throughout the body. In some embodiments, the accumulation of proteins and other cellular products in lysosomes results in damage to cells of the nervous system, including neurons.
- the disease or disorder is associated with or causative of one or more symptoms, including visual impairment, retinal degeneration, intellectual disability, impaired cognitive function, speech impairment, seizures, muscle rigidity or stiffness, hypokinesia, stooped posture, arrhythmia, and impaired motor function.
- the disease or disorder is a neuronal ceroid lipofuscinosis (NCL).
- NCL neuronal ceroid lipofuscinosis
- the disease or disorder is Batten disease.
- the disease or disorder is CLN3 Batten disease.
- a “cell” refers to a cell obtained from a subject or existing within a subject.
- the cell is a cell which produces CLN3 transcripts (e.g., pre- mRNA molecules or mRNA molecules) and/or CLN3 protein.
- the cell may be a cell of the nervous system (e.g., a neuron), or the cell may be a non-neuronal cell (e.g., a skin cell, such as a fibroblast).
- the cell is from a subject having a disease or disorder, such as a neurodegenerative disease or disorder disclosed herein.
- the cell is from a subject having CLN3 Batten disease.
- the cell is contacted with an oligonucleotide (e.g., synthetic oligonucleotide), a SNA, or a composition thereof (e.g., pharmaceutical composition thereof) disclosed herein at a concentration of at least 0.001 nM, at least 0.01 nM, at least 0.1 nM, at least 1 nM, at least 10 nM, at least 100 nM, at least 1000 nM, at least 10 mM, at least 100 mM, at least 1000 mM, or above 1000 mM.
- an oligonucleotide e.g., synthetic oligonucleotide
- SNA e.g., synthetic oligonucleotide
- a composition thereof e.g., pharmaceutical composition thereof
- the cell is contacted with oligonucleotide (e.g., synthetic oligonucleotide), a SNA, or a composition (e.g., pharmaceutical composition) disclosed herein at a concentration range of 0.001 nM to 0.01 nM, 0.01 nM to 0.1 nM, 0.1 nM to 1 nM, 1 nM to 10 nM, 10 nM to 100 nM, 100 nM to 1000 nM, 1000 nM to 10 mM, 10 mM to 100 mM, or 100 mM to 1000 mM.
- oligonucleotide e.g., synthetic oligonucleotide
- SNA e.g., SNA
- a composition e.g., pharmaceutical composition
- the cell is contacted with oligonucleotide (e.g., synthetic oligonucleotide), a SNA, or a composition (e.g., pharmaceutical composition) disclosed herein at a concentration of 0.001 nM, 0.01 nM, 0.1 nM, 1 nM, 10 nM, 100 nM, 1000 nM, 10 mM, 100 mM, 1000 mM or above 1000 mM.
- the concentration refers to the total weight or total mass of an oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein in a volume of solution.
- a concentration of 0.001 nM refers to 0.001 nmoles of oligonucleotide (e.g., synthetic oligonucleotide) per liter of solution (e.g., pharmaceutically acceptable carrier).
- the concentration refers to the total weight or total mass of an SNA disclosed herein in a volume of solution.
- a concentration of 0.001 nM refers to 0.001 nmoles of SNA per liter of solution (e.g., pharmaceutically acceptable carrier).
- ameliorating or eliminating a disease or symptom refers to decreasing the severity of the disease or the symptom or removing evidence of the disease or the symptom in a subject.
- ameliorating or eliminating a disease or symptom may refer to a change in a metric associated with the disease or symptom as evaluated by a medical professional or as measured by a laboratory test.
- ameliorating or eliminating a disease, disorder or symptom may refer to a change in a metric associated with the disease, disorder or symptom as reported by the subject having the disease or symptom.
- ameliorating or eliminating a disease or symptom may refer to a decrease or elimination of one or more neurodegenerative symptoms associated with the disease, disorder or symptom.
- an oligonucleotide e.g., synthetic oligonucleotide
- SNA or pharmaceutically acceptable salt thereof disclosed herein is delivered to the central and/or peripheral nervous system.
- a “second therapeutic agent” refers to a therapeutic agent other than an oligonucleotide (e.g., synthetic oligonucleotide), SNA or composition disclosed herein.
- the second therapeutic agent may refer to any composition, compound, or device that is administered to or utilized on a subject having a disease or disorder, which may enhance the therapeutic effect of the synthetic oligonucleotide or SNA disclosed herein, or which may ameliorate one or more symptoms of the disease or disorder.
- Second therapeutic agents include, but are not limited to antidepressants or other psychiatric medications and anticonvulsants.
- the subject is a mammal.
- the subject is a primate.
- the subject is a human.
- the mammal is a vertebrate animal including, but not limited to, a mouse, rat, dog, cat, horse, cow, pig, sheep, goat, turkey, chicken, monkey, fish (e.g., aquaculture species, salmon, etc.).
- a neurodegenerative disease e.g., a neuronal ceroid lipofuscinosis, such as CLN3 Batten disease
- the disclosure herein can be used to treat a neurodegenerative disease in a human or non-human subject.
- the disclosure herein can be used to treat neuronal ceroid lipofuscinoses in a human or non-human subject.
- the disclosure herein can be used to treat Batten disease in a human or non-human subject.
- the disclosure herein can be used to treat CLN3 Batten disease in a human or non-human subject.
- the oligonucleotide (e.g., synthetic oligonucleotide) and/or SNA is administered in a pharmaceutical composition.
- routes of administration include but are not limited to cutaneous, subcutaneous, nodal, systemic, intravenous, intrathecal, intravitreal, intracisterna magna, intracranial, oral, parenteral, intramuscular, intranasal, sublingual, intratracheal, inhalation, ocular, vaginal, and rectal. Administration may be by any acceptable method, including but not limited to injection, topical administration, ingestion, or inhalation.
- the dose as it relates to administration of an oligonucleotide (e.g., synthetic oligonucleotide) and/or an SNA disclosed herein (e.g., without limitation the phrases “an effective amount of a synthetic oligonucleotide,” “an effective amount of a pharmaceutical composition,” “an effective amount of a spherical nucleic acid”, etc.) refers to the total weight or total mass of active agent (e.g., total weight or total mass of the synthetic oligonucleotides) in the SNA administered to the subject (e.g., subject with a disease or disorder).
- an “effective amount” refers to an amount that is capable of improving one or more symptoms of a disease or disorder or an amount that is capable of improving a metric associated with a disease or disorder.
- a dose disclosed herein is considered a fixed dose or a discrete dose.
- a dose disclosed herein can be adjusted to depend on body weight or be made dependent on body weight.
- a non-limiting example includes a dose of 2 mg of an oligonucleotide (e.g., synthetic oligonucleotide), an SNA, or a composition thereof (e.g., pharmaceutical composition thereof) disclosed herein, that can also be administered as 2 mg/kg body weight, which depends on kg of body weight.
- a dose disclosed herein is independent of body weight.
- a dose disclosed herein can be adjusted to depend on body surface area (e.g., total body surface area, skin surface area to be treated, etc.) or be made dependent on body surface area.
- a non-limiting example includes a dose of 2 mg of an oligonucleotide (e.g., synthetic oligonucleotide), an SNA, or a composition thereof (e.g., pharmaceutical composition thereof) disclosed herein, that can also be administered as 2 mg/m 2 body surface area, which depends on m 2 of body surface area (e.g., total body surface area).
- a dose disclosed herein is independent of body surface area.
- an oligonucleotide e.g., synthetic oligonucleotide
- an SNA or a composition thereof (e.g., pharmaceutical composition thereof) disclosed herein is administered once a day, once every three days, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nice weeks, once every 10 weeks, once every 12 weeks, once every 18 weeks, once every 24 weeks, once a month, once every two months, once every three months, once every four months, once every five months, once every six months, once every seven months, once every eight months, once every nine months, once every 10 months, once every 11 months, once a year, once every two years, once every three years, once every four years.
- an oligonucleotide e.g., synthetic oligonucleotide
- a SNA a composition thereof (e.g., pharmaceutical composition thereof) disclosed herein is administered to a subject once a week, twice a week or three times per week, for four weeks, six weeks, eight weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 24 weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, 10 months, 11 months, one year, two years, three years, four years, five years, six years.
- a composition thereof e.g., pharmaceutical composition thereof
- an oligonucleotide e.g., synthetic oligonucleotide
- a SNA or a composition thereof (e.g., pharmaceutical composition thereof) disclosed herein is administered to a subject every three weeks for four weeks, six weeks, eight weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 24 weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, 10 months, 11 months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, or 10 years.
- the SNA is administered every three weeks.
- the SNA is administered about or at least about every four weeks, five weeks, six weeks, 2 months, three months, six months, nine months, one year, 1.5 years, two years, 2.5 years, three years, 3.5 years, four years, 4.5 years, five years, 5.5 years, or six years.
- the duration of the method for treating a disease or disorder (e.g., CLN3 Batten disease) with an oligonucleotide (e.g., synthetic oligonucleotide), a SNA, or a composition thereof (e.g., pharmaceutical composition thereof) disclosed herein is for about or at least 3 months, for about or at least six months, for about or at least nine months, for about or at least one year, for about or at least 1.5 years, for about or at least two years, for about or at least 2.5 years, for about or at least 3 years, for about or at least 3.5 years, for about or at least 4 years, for about or at least 4.5 years, for about or at least 5 years, for about or at least 5.5 years, for about or at least 6 years, for about or at least 6.5 years, for about or at least 7 years, for about or at least 7.5 years, for about or at least 8 years, for about or at least 8.5 years, for about or at least 9 years, for about or at least 9.5 years,
- an effective amount is from about 0.1 pg to 10,000 mg per dose, at least about 1 pg to 8,000 mg per dose, or 10 pg to 100 pg per dose.
- the dose administered is about or at least about 1 microgram, about or at least about 5 microgram, about or at least about 10 microgram, about or at least about 50 microgram, about or at least about 100 micro gram, about or at least about 200 microgram, about or at least about 350 microgram, about or at least about 500 microgram, about or at least about 1 milligram, about or at least about 5 milligram, about or at least about 10 milligram, about or at least about 50 milligram, about or at least about 100 milligram, about or at least about 200 milligram, about or at least about 350 milligram, about or at least about 500 milligram, about or at least about 1000 mg or more per dose, and any range or combination thereof.
- the dose administered is about or at least about 1 microgram/kg of body weight, about or at least about 5 microgram/kg of body weight, about or at least about 10 microgram/kg of body weight, about or at least about 50 microgram/kg of body weight, about or at least about 100 microgram/kg of body weight, about or at least about 200 microgram/kg of body weight, about or at least about 350 microgram/kg of body weight, about or at least about 500 microgram/kg of body weight, about or at least about 1 milligram/kg of body weight, about or at least about 5 milligram/kg of body weight, about or at least about 10 milligram/kg of body weight, about or at least about 50 milligram/kg of body weight, about or at least about 100 milligram/kg of body weight, about or at least about 200 milligram/kg of body weight, about or at least about 350 milligram/kg of body weight, about or at least about 500 milligram/kg of body weight, to about or at least about at least about
- a range of about 5 mg/kg of body weight to about 100 mg/kg of body weight, about 5 microgram/kg of body weight to about 500 milligram/kg of body weight, etc. can be administered, based on the numbers disclosed above.
- the absolute amount (e.g., a discrete dose) will depend upon a variety of factors including the concurrent treatment, the number of doses and the individual patient parameters including age, physical condition, size and weight. These are factors well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical judgment.
- an oligonucleotide e.g., a synthetic oligonucleotide
- an SNA or composition thereof (e.g., pharmaceutical composition thereof) disclosed herein is administered at a dose between 0.1 mg and 10 mg, between 0.2 mg and 10 mg, between 0.3 mg and 10 mg, between 0.4 mg and 10 mg, between 0.5 mg and 10 mg, between 0.6 mg and 10 mg, between 0.7 mg and 10 mg, between 0.8 mg and 10 mg, between 0.9 mg and 10 mg, between 1 mg and 10 mg, between 1 mg and 1,000 mg, between 1 mg and 900 mg, between 1 mg and 800 mg, between 1 mg and 700 mg, between 1 mg and 600 mg, between 1 mg and 500 mg, between 1 mg and 450 mg, between 1 mg and 400 mg, between 1 mg and 350 mg, between 1 mg and 300 mg, between 1 mg and 250 mg, between 1 mg and 200 mg, between 1 mg and 150 mg, between 1 mg and 100 mg, between 1 mg and 90 mg, between 1 mg and 80 mg, between 1 mg and
- an oligonucleotide e.g., a synthetic oligonucleotide
- an SNA or composition thereof (e.g., pharmaceutical composition thereof) disclosed herein is administered at a dose of or about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10
- an oligonucleotide e.g., a synthetic oligonucleotide
- an SNA or composition thereof (e.g., pharmaceutical composition thereof) disclosed herein is administered at a dose of at least or at least about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg,
- an oligonucleotide e.g., a synthetic oligonucleotide
- an SNA or composition thereof (e.g., pharmaceutical composition) disclosed herein is administered at a dose greater than or greater than about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg,
- “pharmaceutically acceptable salts” are physiologically and pharmaceutically acceptable salts of the nucleic acids (e.g., salts that retain the desired biological activity of the compound of interest and do not impart undesired toxicological effects thereto).
- Pharmaceutically acceptable salts include but are not limited to (a) salts formed with cations such as sodium, potassium, ammonium, magnesium, calcium, polyamines such as spermine and spermidine, etc.; (b) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; (c) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, na
- compositions of the present disclosure comprise an effective amount of one or more agents, dissolved or dispersed in a pharmaceutically acceptable carrier.
- salts include the acid addition salts, e.g., those formed with the free amino groups of a proteinaceous composition, or which are formed with inorganic acids such as for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric or mandelic acid. Salts formed with the free carboxyl groups also can be derived from inorganic bases such as for example, sodium, potassium, ammonium, calcium or ferric hydroxides; or such organic bases as isopropylamine, trimethylamine, histidine or procaine.
- inorganic acids such as for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric or mandelic acid.
- Salts formed with the free carboxyl groups also can be derived from inorganic bases such as for example, sodium, potassium, ammonium, calcium or ferric hydroxides; or such organic bases as isopropylamine, trimethylamine, histidine or procaine
- a carrier can be a solvent or dispersion medium comprising but not limited to, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), lipids (e.g., triglycerides, vegetable oils, liposomes) and combinations thereof.
- the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin; by the maintenance of the required particle size by dispersion in carriers such as, for example liquid polyol or lipids; by the use of surfactants such as, for example hydroxypropylcellulose; or combinations thereof such methods.
- isotonic agents such as, for example, sugars, sodium chloride or combinations thereof.
- a “pharmaceutical or pharmacologically acceptable” composition refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate.
- animal e.g., human
- preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biological Standards.
- the compounds are generally suitable for administration to humans. This term requires that a compound or composition be nontoxic and sufficiently pure so that no further manipulation of the compound or composition is needed prior to administration to humans.
- compositions may comprise, for example, at least about 0.000001% (w/w) of an active agent (e.g., an oligonucleotide, such as a synthetic oligonucleotide, or an SNA disclosed herein).
- an active agent e.g., an oligonucleotide, such as a synthetic oligonucleotide, or an SNA disclosed herein.
- the active compound may comprise between about 2% to about 75% of the weight of the unit (w/w), or between about 25% to about 60%, for example, and any range or combination thereof.
- the active agent e.g., an oligonucleotide, such as a synthetic oligonucleotide, or an SNA disclosed herein
- the active agent comprises between 0.000001% and 0.00001%, between 0.00001% and 0.0001%, between 0.0001% and 0.001%, between 0.001% and 0.01%, between 0.01% and 0.1%, between 0.1% and 1%, between 1% and 5%, between 5% and 10%, between 10% and 15%, between 15% and 20%, between 20% and 25%, between 25% and 30%, between 30% and 40%, between 40% and 50% (w/w), and any range or combination thereof.
- the active agent e.g., oligonucleotide, such as a synthetic oligonucleotide or an SNA disclosed herein
- the active agent comprises 0.00007%, 0.007%, 0.01%, 0.1%, 1% (w/w).
- compositions comprising one or more oligonucleotide (e.g., a synthetic oligonucleotide disclosed herein).
- pharmaceutical compositions comprising one or more SNA.
- the oligonucleotides comprised within the one or more SNA each consist of a modified oligonucleotide.
- the pharmaceutical composition comprises a pharmaceutically acceptable diluent or carrier.
- a pharmaceutical composition comprises or consists of a sterile saline solution and one or more SNA.
- the sterile saline is pharmaceutical grade saline.
- a pharmaceutical composition comprises or consists of one or more SNA and sterile water.
- the sterile water is pharmaceutical grade water.
- a pharmaceutical composition comprises or consists of one or more SNA and phosphate-buffered saline (PBS).
- the sterile PBS is pharmaceutical grade PBS.
- a pharmaceutical composition comprises a modified SNA and artificial cerebrospinal fluid.
- a pharmaceutical composition consists of an SNA and artificial cerebrospinal fluid.
- a pharmaceutical composition consists essentially of an SNA and artificial cerebrospinal fluid.
- the artificial cerebrospinal fluid is pharmaceutical grade.
- artificial cerebrospinal fluid contains sodium dihydrogen phosphate dihydrate, sodium phosphate dibasic anhydrous, sodium chloride, potassium chloride, calcium chloride dihydrate, magnesium chloride hexahydrate, a suitable acid and base to balance pH, and water.
- each 1 mL of artificial cerebrospinal fluid contains:
- compositions comprise one or more SNA and one or more excipients.
- excipients are selected from water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, dextrose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.
- SNA may be admixed with pharmaceutically acceptable active and/or inert substances for the preparation of pharmaceutical compositions or formulations.
- Compositions and methods for the formulation of pharmaceutical compositions depend on a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.
- compositions comprising an SNA encompass any pharmaceutically acceptable salts of the oligonucleotide, esters of the oligonucleotide, or salts of such esters.
- modified oligonucleotides or SNA are in aqueous solution with sodium.
- modified oligonucleotides or SNA are in aqueous solution with potassium.
- modified oligonucleotides or SNA are in PBS.
- modified oligonucleotides or SNA are in water.
- the pH of the solution is adjusted with NaOH and/or HC 1 to achieve a desired pH.
- compositions comprise one or more tissue-specific delivery molecules designed to deliver the one or more pharmaceutical agents of the present invention to specific tissues or cell types.
- pharmaceutical compositions include a tissue-specific antibody.
- compositions comprise a co-solvent system.
- co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
- co-solvent systems are used for hydrophobic compounds.
- a non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM and 65% w/v polyethylene glycol 300.
- the proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics.
- co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80TM; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
- “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art.
- the agent may comprise different types of carriers depending on whether it is to be administered in solid, liquid, gel, cream, or aerosol form, and whether it need to be sterile for such routes of administration as injection.
- An oligonucleotide e.g., synthetic oligonucleotide
- SNA or compositions thereof (e.g., pharmaceutical composition thereof) disclosed herein can be administered intravenously, intradermally, intraarterially, intralesionally, intratumorally, intracranially, intrathecally, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intramuscularly, intraperitoneally, subcutaneously, subconjunctival, intravascularly, mucosally, intrapericardially, intraumbilically, intraocularly (e.g., intravitreally), via intracisterna magna injection, via eyedrops, orally, topically (e.g., cutaneously), locally, via inhalation (e.g., aerosol inhalation), via injection, via infusion, via continuous infusion, via localized perfusion bathing target cells directly, via
- an oligonucleotide e.g., synthetic oligonucleotide
- SNA or compositions thereof (e.g., pharmaceutical composition thereof) disclosed herein
- an oligonucleotide e.g., synthetic oligonucleotide
- an SNA or a composition thereof (e.g., pharmaceutical composition thereof) disclosed herein
- an oligonucleotide e.g., synthetic oligonucleotide
- an SNA or a composition thereof (e.g., pharmaceutical composition thereof) disclosed herein is administered to the eye, such as by intravitreal injection.
- an oligonucleotide e.g., synthetic oligonucleotide
- an SNA or a composition thereof (e.g., pharmaceutical composition thereof) disclosed here
- an oligonucleotide, SNA, or composition thereof is administered both into the central nervous system and to the eye
- such administrations may be substantially at the same time (e.g., within the same hour or on the same day, etc.), or may be temporally separated (e.g., a day or more apart, a week or more apart, etc.).
- compositions are prepared for oral administration.
- pharmaceutical compositions are prepared for buccal administration.
- a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, intrathecal (IT), intracerebroventricular (ICV), intracisterna magna (ICM), intravitreal, etc.).
- a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
- other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
- injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like.
- Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers.
- Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.
- the composition may comprise various antioxidants to retard oxidation of one or more components.
- the prevention of the action of microorganisms can be brought about by preservatives such as various antibacterial and antifungal agents, including but not limited to parabens (e.g., methylparabens, propylparabens), chlorobutanol, phenol, sorbic acid, thimerosal or combinations thereof.
- parabens e.g., methylparabens, propylparabens
- chlorobutanol phenol
- sorbic acid thimerosal or combinations thereof.
- the agent which may be an oligonucleotide (e.g., synthetic oligonucleotide), SNA, or compositions thereof (e.g., pharmaceutical composition thereof) as disclosed, may be formulated into a composition in a free base, neutral or salt form.
- An oligonucleotide e.g., synthetic oligonucleotide
- SNA or compositions thereof (e.g., pharmaceutical composition thereof) disclosed herein may be administered directly to a tissue.
- Direct tissue administration may be achieved by direct injection, topical application, or local application.
- the compounds may be administered once, or alternatively they may be administered in a plurality of administrations. If administered multiple times, the compounds may be administered via different routes. For example, the first (or the first few) administrations may be made directly into the affected tissue while later administrations may be systemic.
- compositions are administered in pharmaceutically acceptable compositions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, excipients, and optionally other therapeutic ingredients.
- a composition disclosed herein e.g., synthetic oligonucleotide,
- a pharmaceutical composition comprises the composition and a pharmaceutically-acceptable carrier.
- a pharmaceutically-acceptable carrier means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients.
- Pharmaceutically acceptable carriers include, without limitation, diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials which are well-known in the art. Such preparations may routinely contain salt, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents.
- the salts When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically-acceptable salts thereof and are not excluded from the scope of the disclosure.
- Such pharmacologically and pharmaceutically-acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like.
- pharmaceutically-acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.
- composition disclosed herein e.g., oligonucleotide, synthetic oligonucleotide,
- SNA small cell lung cancer
- SNA small cell lung cancer
- preparations in solid, semi-solid, liquid or gaseous forms such as tablets, capsules, powders, granules, ointments, solutions, depositories, inhalants and injections, and usual ways for oral, parenteral or surgical administration.
- the disclosure also embraces pharmaceutical compositions which are formulated for local administration, such as by implants.
- a composition disclosed herein when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
- Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
- the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
- non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
- Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
- Parenteral vehicles include sodium chloride solution, Ringer’s dextrose, dextrose and sodium chloride, lactated Ringer’s, or fixed oils.
- Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer’s dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like. Lower doses will result from other forms of administration, such as intravenous administration. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of compounds.
- a delivery vehicle is a biocompatible microparticle or implant that is suitable for implantation into the mammalian recipient.
- Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the compound, increasing convenience to the subject and the physician.
- Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer base systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides.
- inventive embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed.
- inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein.
- a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
- the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
- This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified.
- “at least one of A and B” can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one,
- Spherical nucleic acids (SNAs) bearing oligonucleotides complementary to select regions of the pre-mRNA expressed from human CLN3 gene (NCBI RefSeq NG_008654.2, SEQ ID NO: 1) were tested.
- the synthetic oligonucleotides used in accordance with this invention may be conveniently and routinely made through the well-known technique of solid phase synthesis.
- the oligonucleotides listed in Table 1 were synthesized on an automated DNA synthesizer using commercially available reagents and the appropriate phosphor amidite chemistry. The oligonucleotides were deprotected and isolated to desired purity and used to prepare SNA compounds.
- the oligonucleotides provided in Table 1 were uniformly 2’-MOE modified, with each internucleoside linkage being a phosphorothioate linkage.
- Each cytosine base was a 5-methyl cytosine, and select guanosine residues were replaced with 7-Deaza deoxyguanosine.
- the oligonucleotides contained the lipophilic linker cholesterol- triethyleneglycol (CholTEG) at the 3’ end.
- the linker was attached to the nucleobase portion of the synthetic oligonucleotide via a spacer consisting of two hexaethylene glycols (HEG, iSp 18) linked via phosphodiester linkages.
- SNAs Liposomes synthesized from DOPC and having a mean diameter of about 20 nanometers were used as cores to prepare SNAs.
- SNAs were prepared by mixing one population of synthetic oligonucleotides with the DOPC liposomes at lipid to oligonucleotide molar ratio of about 50 to 1. Oligonucleotides were anchored via their 3’ ends to the exterior surface of the liposome core by the lipophilic linker to produce the SNA structure.
- the synthetic oligonucleotides of each SNA target the pre-mRNA expressed from human CLN3 gene.
- the start sites listed in Table 1 associated with each oligonucleotide are the 5’ positions of the portion of SEQ ID NO: 1 to which each oligonucleotide is complementary.
- a CLN3 A78/A78 patient fibroblast cell line (BAT_055, National Institutes of Health) was used. This cell line is homozygous for the most common 1.02 kb deletion in exons 7 and 8 of human CLN3 mRNA. Cells were seeded at 10,000 cells per well in 96 well plates. Approximately 24 hours after plating, SNAs diluted in sterile PBS were added directly to wells to achieve a final treatment concentration of 2000 nM of oligonucleotide.
- PCR products were resolved on TapeStation dlOOO tapes (Agilent), and the optical density of the spliced product (A “targeted-exon” + D78) was divided by the optical density of the unmodified product (D78) for each sample, to generate an edit ratio.
- D578 PCR products lacking exons 5, 7 and 8
- D78 PCR products lacking only exons 7 and 8
- mice express a CLN3 locus in which exons 7 and 8 have been deleted (CLN3Aexon7/8), resulting in non-functional CLN3.
- CLN3Aexon7/8 mice were treated with CLN3 -targeting SNAs or vehicle via intravitreal injection.
- CLN3 mRNA levels were measured in the retinae of the SNA-treated CLN3Aexon7/8 mice and compared with vehicle treated CLN3Aexon7/8 mice, untreated wild-type mice (i.e., mice with wild-type CLN3 alleles, not the CLN3Aexon7/8 allele), and untreated heterozygous mutant mice (i.e., mice with one copy of the CLN3Aexon7/8 allele).
- Spherical nucleic acids (SNAs) bearing oligonucleotides complementary to the pre- mRNA expressed from the murine CLN3 gene (SEQ ID NO: 773) were tested.
- the synthetic oligonucleotide used in accordance with this invention may be conveniently and routinely made through the well-known technique of solid phase synthesis.
- the modified oligonucleotide listed in Table 2 were synthesized on an automated DNA synthesizer using commercially available reagents and the appropriate phosphoramidite chemistry.
- the oligonucleotide was deprotected and isolated to desired purity and used to prepare the SNA compound.
- Each cytosine base was a 5-methyl cytosine.
- the oligonucleotide contained the lipophilic linker cholesterol-triethyleneglycol (CholTEG) at the 3’ end.
- the linker was attached to the nucleobase portion of the synthetic oligonucleotide via a spacer consisting of two hexaethylene glycols (HEG, iSp 18) linked via phosphodiester linkages.
- HOG, iSp 18 hexaethylene glycols
- Liposomes synthesized from DOPC and having a mean diameter of about 20 nanometers were used as cores to prepare the SNA.
- the SNA was prepared by mixing one population of synthetic oligonucleotides with the DOPC liposomes at lipid to oligonucleotide molar ratio of about 50 to 1.
- Oligonucleotides were anchored via their 3’ ends to the exterior surface of the liposome core by the lipophilic linker to produce the SNA structure.
- the start site listed in Table 2 is the 5’-position of the portion of SEQ ID NO: 773 to which each oligonucleotide is complementary.
- Embodiment 1 A synthetic oligonucleotide comprising a nucleic acid sequence of 12 to 50 linked nucleosides, wherein the nucleic acid sequence is at least 70% complementary to an equal length portion of a CLN3 RNA, and wherein the synthetic oligonucleotide comprises at least one modification selected from a modified sugar, a sugar surrogate, a modified internucleoside linkage, a spacer and a linker.
- Embodiment 2 A synthetic oligonucleotide comprising a nucleic acid sequence of 12 to 50 linked nucleosides having a nucleobase sequence comprising at least 12, 13, 14, 15, or 16 consecutive nucleobases of any one of SEQ ID NO: 11-772.
- Embodiment 3 A synthetic oligonucleotide comprising a nucleic acid sequence of 12 to 50 linked nucleosides having a nucleobase sequence complementary to at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases of an equal length portion of nucleobases 9,462-9,947 of SEQ ID NO: 1 or an equal length portion of nucleobases 13,185-13,397 of SEQ ID NO: 1.
- Embodiment 4 The synthetic oligonucleotide of any one of Embodiments 1-3, wherein the synthetic oligonucleotide comprises at least one modified nucleoside.
- Embodiment 5 The synthetic oligonucleotide of any one of Embodiments 1-4, wherein the synthetic oligonucleotide comprises at least one modified sugar moiety.
- Embodiment 6 The synthetic oligonucleotide of Embodiment 5, wherein the modified sugar moiety is a 2’ -modified sugar moiety.
- Embodiment 7 The synthetic oligonucleotide of Embodiment 6, wherein the 2’-modified sugar moiety is a 2’-O-methoxyethyl (2’-MOE) modified sugar moiety.
- Embodiment 8 The synthetic oligonucleotide of any one of Embodiments 1-7, wherein the synthetic oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety having a 2’-4’ bridge, wherein the 2’-4’ bridge is selected from -O- CH2- and -O-CH(CH3)-.
- Embodiment 9 The synthetic oligonucleotide of any one of Embodiments 1-8, wherein the synthetic oligonucleotide comprises at least one modified nucleoside comprising a non-bicyclic modified sugar moiety.
- Embodiment 10 The synthetic oligonucleotide of any one of embodiments 1-9, wherein the synthetic oligonucleotide comprises at least one modified nucleoside comprising a sugar surrogate.
- Embodiment 11 The synthetic oligonucleotide of embodiment 10, wherein the sugar surrogate is a morpholino or a peptide nucleic acid (PNA).
- the sugar surrogate is a morpholino or a peptide nucleic acid (PNA).
- Embodiment 12 A synthetic oligonucleotide comprising an antisense oligonucleotide listed in Table 1, or a pharmaceutically acceptable salt thereof.
- Embodiment 13 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 13, or a pharmaceutically acceptable salt thereof.
- Embodiment 14 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 17, or a pharmaceutically acceptable salt thereof.
- Embodiment 15 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 24, or a pharmaceutically acceptable salt thereof.
- Embodiment 16 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 27, or a pharmaceutically acceptable salt thereof.
- Embodiment 17 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 31, or a pharmaceutically acceptable salt thereof.
- Embodiment 18 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 34, or a pharmaceutically acceptable salt thereof.
- Embodiment 19 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 35, or a pharmaceutically acceptable salt thereof.
- Embodiment 20 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 41, or a pharmaceutically acceptable salt thereof.
- Embodiment 21 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 44, or a pharmaceutically acceptable salt thereof.
- Embodiment 22 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 45, or a pharmaceutically acceptable salt thereof.
- Embodiment 23 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 48, or a pharmaceutically acceptable salt thereof.
- Embodiment 24 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 51, or a pharmaceutically acceptable salt thereof.
- Embodiment 25 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 53, or a pharmaceutically acceptable salt thereof.
- Embodiment 26 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 55, or a pharmaceutically acceptable salt thereof.
- Embodiment 27 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 56, or a pharmaceutically acceptable salt thereof.
- Embodiment 28 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 62, or a pharmaceutically acceptable salt thereof.
- Embodiment 29 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 66, or a pharmaceutically acceptable salt thereof.
- Embodiment 30 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 67, or a pharmaceutically acceptable salt thereof.
- Embodiment 31 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 70, or a pharmaceutically acceptable salt thereof.
- Embodiment 32 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 71, or a pharmaceutically acceptable salt thereof.
- Embodiment 33 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 72, or a pharmaceutically acceptable salt thereof.
- Embodiment 34 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 75, or a pharmaceutically acceptable salt thereof.
- Embodiment 35 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 76, or a pharmaceutically acceptable salt thereof.
- Embodiment 36 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 77, or a pharmaceutically acceptable salt thereof.
- Embodiment 37 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 79, or a pharmaceutically acceptable salt thereof.
- Embodiment 38 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 80, or a pharmaceutically acceptable salt thereof.
- Embodiment 39 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 81, or a pharmaceutically acceptable salt thereof.
- Embodiment 40 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 82, or a pharmaceutically acceptable salt thereof.
- Embodiment 41 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 83, or a pharmaceutically acceptable salt thereof.
- Embodiment 42 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 84, or a pharmaceutically acceptable salt thereof.
- Embodiment 43 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 85, or a pharmaceutically acceptable salt thereof.
- Embodiment 44 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 86, or a pharmaceutically acceptable salt thereof.
- Embodiment 45 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 87, or a pharmaceutically acceptable salt thereof.
- Embodiment 46 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 88, or a pharmaceutically acceptable salt thereof.
- Embodiment 47 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 89, or a pharmaceutically acceptable salt thereof.
- Embodiment 48 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 90, or a pharmaceutically acceptable salt thereof.
- Embodiment 49 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 91, or a pharmaceutically acceptable salt thereof.
- Embodiment 50 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 92, or a pharmaceutically acceptable salt thereof.
- Embodiment 51 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 94, or a pharmaceutically acceptable salt thereof.
- Embodiment 52 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 95, or a pharmaceutically acceptable salt thereof.
- Embodiment 53 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 96, or a pharmaceutically acceptable salt thereof.
- Embodiment 54 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 97, or a pharmaceutically acceptable salt thereof.
- Embodiment 55 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 98, or a pharmaceutically acceptable salt thereof.
- Embodiment 56 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 99, or a pharmaceutically acceptable salt thereof.
- Embodiment 57 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 103, or a pharmaceutically acceptable salt thereof.
- Embodiment 58 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 105, or a pharmaceutically acceptable salt thereof.
- Embodiment 59 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 106, or a pharmaceutically acceptable salt thereof.
- Embodiment 60 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 108, or a pharmaceutically acceptable salt thereof.
- Embodiment 61 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 111, or a pharmaceutically acceptable salt thereof.
- Embodiment 62 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 112, or a pharmaceutically acceptable salt thereof.
- Embodiment 63 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 114, or a pharmaceutically acceptable salt thereof.
- Embodiment 64 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 115, or a pharmaceutically acceptable salt thereof.
- Embodiment 65 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 116, or a pharmaceutically acceptable salt thereof.
- Embodiment 66 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 117, or a pharmaceutically acceptable salt thereof.
- Embodiment 67 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 118, or a pharmaceutically acceptable salt thereof.
- Embodiment 68 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 120, or a pharmaceutically acceptable salt thereof.
- Embodiment 69 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 121, or a pharmaceutically acceptable salt thereof.
- Embodiment 70 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 122, or a pharmaceutically acceptable salt thereof.
- Embodiment 71 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 124, or a pharmaceutically acceptable salt thereof.
- Embodiment 72 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 126, or a pharmaceutically acceptable salt thereof.
- Embodiment 73 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 127, or a pharmaceutically acceptable salt thereof.
- Embodiment 74 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 128, or a pharmaceutically acceptable salt thereof.
- Embodiment 75 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 129, or a pharmaceutically acceptable salt thereof.
- Embodiment 76 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 130, or a pharmaceutically acceptable salt thereof.
- Embodiment 77 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 131, or a pharmaceutically acceptable salt thereof.
- Embodiment 78 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 132, or a pharmaceutically acceptable salt thereof.
- Embodiment 79 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 133, or a pharmaceutically acceptable salt thereof.
- Embodiment 80 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 134, or a pharmaceutically acceptable salt thereof.
- Embodiment 81 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 135, or a pharmaceutically acceptable salt thereof.
- Embodiment 82 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 136, or a pharmaceutically acceptable salt thereof.
- Embodiment 83 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 137, or a pharmaceutically acceptable salt thereof.
- Embodiment 84 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 138, or a pharmaceutically acceptable salt thereof.
- Embodiment 85 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 139, or a pharmaceutically acceptable salt thereof.
- Embodiment 86 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 140, or a pharmaceutically acceptable salt thereof.
- Embodiment 87 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 141, or a pharmaceutically acceptable salt thereof.
- Embodiment 88 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 143, or a pharmaceutically acceptable salt thereof.
- Embodiment 89 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 144, or a pharmaceutically acceptable salt thereof.
- Embodiment 90 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 145, or a pharmaceutically acceptable salt thereof.
- Embodiment 91 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 146, or a pharmaceutically acceptable salt thereof.
- Embodiment 92 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 147, or a pharmaceutically acceptable salt thereof.
- Embodiment 93 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 149, or a pharmaceutically acceptable salt thereof.
- Embodiment 94 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 150, or a pharmaceutically acceptable salt thereof.
- Embodiment 95 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 151, or a pharmaceutically acceptable salt thereof.
- Embodiment 96 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 153, or a pharmaceutically acceptable salt thereof.
- Embodiment 97 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 154, or a pharmaceutically acceptable salt thereof.
- Embodiment 98 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 155, or a pharmaceutically acceptable salt thereof.
- Embodiment 99 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 156, or a pharmaceutically acceptable salt thereof.
- Embodiment 100 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 157, or a pharmaceutically acceptable salt thereof.
- Embodiment 101 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 159, or a pharmaceutically acceptable salt thereof.
- Embodiment 102 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 160, or a pharmaceutically acceptable salt thereof.
- Embodiment 103 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 161, or a pharmaceutically acceptable salt thereof.
- Embodiment 104 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 162, or a pharmaceutically acceptable salt thereof.
- Embodiment 105 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 163, or a pharmaceutically acceptable salt thereof.
- Embodiment 106 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 164, or a pharmaceutically acceptable salt thereof.
- Embodiment 107 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 166, or a pharmaceutically acceptable salt thereof.
- Embodiment 108 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 167, or a pharmaceutically acceptable salt thereof.
- Embodiment 109 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 168, or a pharmaceutically acceptable salt thereof.
- Embodiment 110 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 169, or a pharmaceutically acceptable salt thereof.
- Embodiment 11E A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 170, or a pharmaceutically acceptable salt thereof.
- Embodiment 112 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 171, or a pharmaceutically acceptable salt thereof.
- Embodiment 113 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 172, or a pharmaceutically acceptable salt thereof.
- Embodiment 114 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 173, or a pharmaceutically acceptable salt thereof.
- Embodiment 115 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 174, or a pharmaceutically acceptable salt thereof.
- Embodiment 116 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 175, or a pharmaceutically acceptable salt thereof.
- Embodiment 117 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 176, or a pharmaceutically acceptable salt thereof.
- Embodiment 118 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 178, or a pharmaceutically acceptable salt thereof.
- Embodiment 119 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 180, or a pharmaceutically acceptable salt thereof.
- Embodiment 120 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 181, or a pharmaceutically acceptable salt thereof.
- Embodiment 121 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 182, or a pharmaceutically acceptable salt thereof.
- Embodiment 122 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 187, or a pharmaceutically acceptable salt thereof.
- Embodiment 123 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 188, or a pharmaceutically acceptable salt thereof.
- Embodiment 124 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 190, or a pharmaceutically acceptable salt thereof.
- Embodiment 125 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 195, or a pharmaceutically acceptable salt thereof.
- Embodiment 126 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 198, or a pharmaceutically acceptable salt thereof.
- Embodiment 127 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 199, or a pharmaceutically acceptable salt thereof.
- Embodiment 128 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 224, or a pharmaceutically acceptable salt thereof.
- Embodiment 129 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 227, or a pharmaceutically acceptable salt thereof.
- Embodiment 130 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 228, or a pharmaceutically acceptable salt thereof.
- Embodiment 131 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 229, or a pharmaceutically acceptable salt thereof.
- Embodiment 132 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 233, or a pharmaceutically acceptable salt thereof.
- Embodiment 133 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 238, or a pharmaceutically acceptable salt thereof.
- Embodiment 134 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 239, or a pharmaceutically acceptable salt thereof.
- Embodiment 135. A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 240, or a pharmaceutically acceptable salt thereof.
- Embodiment 136 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 241, or a pharmaceutically acceptable salt thereof.
- Embodiment 137 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 242, or a pharmaceutically acceptable salt thereof.
- Embodiment 138 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 244, or a pharmaceutically acceptable salt thereof.
- Embodiment 139 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 250, or a pharmaceutically acceptable salt thereof.
- Embodiment 140 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 270, or a pharmaceutically acceptable salt thereof.
- Embodiment 141 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 273, or a pharmaceutically acceptable salt thereof.
- Embodiment 142 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 275, or a pharmaceutically acceptable salt thereof.
- Embodiment 143 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 276, or a pharmaceutically acceptable salt thereof.
- Embodiment 144 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 278, or a pharmaceutically acceptable salt thereof.
- Embodiment 145 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 279, or a pharmaceutically acceptable salt thereof.
- Embodiment 146 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 282, or a pharmaceutically acceptable salt thereof.
- Embodiment 147 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 283, or a pharmaceutically acceptable salt thereof.
- Embodiment 148 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 286, or a pharmaceutically acceptable salt thereof.
- Embodiment 149 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 287, or a pharmaceutically acceptable salt thereof.
- Embodiment 150 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 288, or a pharmaceutically acceptable salt thereof.
- Embodiment 151 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 289, or a pharmaceutically acceptable salt thereof.
- Embodiment 152 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 291, or a pharmaceutically acceptable salt thereof.
- Embodiment 153 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 293, or a pharmaceutically acceptable salt thereof.
- Embodiment 154 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 294, or a pharmaceutically acceptable salt thereof.
- Embodiment 155 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 295, or a pharmaceutically acceptable salt thereof.
- Embodiment 156 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 297, or a pharmaceutically acceptable salt thereof.
- Embodiment 157 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 298, or a pharmaceutically acceptable salt thereof.
- Embodiment 158 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 299, or a pharmaceutically acceptable salt thereof.
- Embodiment 159 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 304, or a pharmaceutically acceptable salt thereof.
- Embodiment 160 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 305, or a pharmaceutically acceptable salt thereof.
- Embodiment 161 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 306, or a pharmaceutically acceptable salt thereof.
- Embodiment 162 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 307, or a pharmaceutically acceptable salt thereof.
- Embodiment 163 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 308, or a pharmaceutically acceptable salt thereof.
- Embodiment 164 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 310, or a pharmaceutically acceptable salt thereof.
- Embodiment 165 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 313, or a pharmaceutically acceptable salt thereof.
- Embodiment 166 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 316, or a pharmaceutically acceptable salt thereof.
- Embodiment 167 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 322, or a pharmaceutically acceptable salt thereof.
- Embodiment 168 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 323, or a pharmaceutically acceptable salt thereof.
- Embodiment 169 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 335, or a pharmaceutically acceptable salt thereof.
- Embodiment 170 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 338, or a pharmaceutically acceptable salt thereof.
- Embodiment 171 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 339, or a pharmaceutically acceptable salt thereof.
- Embodiment 172 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 344, or a pharmaceutically acceptable salt thereof.
- Embodiment 173 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 347, or a pharmaceutically acceptable salt thereof.
- Embodiment 174 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 354, or a pharmaceutically acceptable salt thereof.
- Embodiment 175. A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 335, or a pharmaceutically acceptable salt thereof.
- Embodiment 176 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 357, or a pharmaceutically acceptable salt thereof.
- Embodiment 177 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 358, or a pharmaceutically acceptable salt thereof.
- Embodiment 178 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 360, or a pharmaceutically acceptable salt thereof.
- Embodiment 179 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 363, or a pharmaceutically acceptable salt thereof.
- Embodiment 180 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 366, or a pharmaceutically acceptable salt thereof.
- Embodiment 181 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 367, or a pharmaceutically acceptable salt thereof.
- Embodiment 182 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 370, or a pharmaceutically acceptable salt thereof.
- Embodiment 183 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 372, or a pharmaceutically acceptable salt thereof.
- Embodiment 184 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 383, or a pharmaceutically acceptable salt thereof.
- Embodiment 185 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 387, or a pharmaceutically acceptable salt thereof.
- Embodiment 186 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 389, or a pharmaceutically acceptable salt thereof.
- Embodiment 187 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 390, or a pharmaceutically acceptable salt thereof.
- Embodiment 188 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 392, or a pharmaceutically acceptable salt thereof.
- Embodiment 189 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 395, or a pharmaceutically acceptable salt thereof.
- Embodiment 190 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 396, or a pharmaceutically acceptable salt thereof.
- Embodiment 191 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 397, or a pharmaceutically acceptable salt thereof.
- Embodiment 192 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 398, or a pharmaceutically acceptable salt thereof.
- Embodiment 193 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 405, or a pharmaceutically acceptable salt thereof.
- Embodiment 194 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 407, or a pharmaceutically acceptable salt thereof.
- Embodiment 195 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 425, or a pharmaceutically acceptable salt thereof.
- Embodiment 196 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 426, or a pharmaceutically acceptable salt thereof.
- Embodiment 197 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 431, or a pharmaceutically acceptable salt thereof.
- Embodiment 198 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 452, or a pharmaceutically acceptable salt thereof.
- Embodiment 199 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 453, or a pharmaceutically acceptable salt thereof.
- Embodiment 200 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 459, or a pharmaceutically acceptable salt thereof.
- Embodiment 201 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 464, or a pharmaceutically acceptable salt thereof.
- Embodiment 202 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 465, or a pharmaceutically acceptable salt thereof.
- Embodiment 203 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 483, or a pharmaceutically acceptable salt thereof.
- Embodiment 204 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 486, or a pharmaceutically acceptable salt thereof.
- Embodiment 205 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 513, or a pharmaceutically acceptable salt thereof.
- Embodiment 206 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 519 or a pharmaceutically acceptable salt thereof.
- Embodiment 207 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 522, or a pharmaceutically acceptable salt thereof.
- Embodiment 208 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 549, or a pharmaceutically acceptable salt thereof.
- Embodiment 209 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 555, or a pharmaceutically acceptable salt thereof.
- Embodiment 210 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 561, or a pharmaceutically acceptable salt thereof.
- Embodiment 211 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 579, or a pharmaceutically acceptable salt thereof.
- Embodiment 212 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 609, or a pharmaceutically acceptable salt thereof.
- Embodiment 21 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 627, or a pharmaceutically acceptable salt thereof.
- Embodiment 214 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 630, or a pharmaceutically acceptable salt thereof.
- Embodiment 215. A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 636, or a pharmaceutically acceptable salt thereof.
- Embodiment 216 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 660, or a pharmaceutically acceptable salt thereof.
- Embodiment 217 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 663, or a pharmaceutically acceptable salt thereof.
- Embodiment 218 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 666, or a pharmaceutically acceptable salt thereof.
- Embodiment 21 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 675, or a pharmaceutically acceptable salt thereof.
- Embodiment 220 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 678, or a pharmaceutically acceptable salt thereof.
- Embodiment 22 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 681, or a pharmaceutically acceptable salt thereof.
- Embodiment 222 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 683, or a pharmaceutically acceptable salt thereof.
- Embodiment 223. A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 686, or a pharmaceutically acceptable salt thereof.
- Embodiment 224 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 692, or a pharmaceutically acceptable salt thereof.
- Embodiment 225 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 696, or a pharmaceutically acceptable salt thereof.
- Embodiment 226 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 697, or a pharmaceutically acceptable salt thereof.
- Embodiment 227 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 699, or a pharmaceutically acceptable salt thereof.
- Embodiment 228 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 738, or a pharmaceutically acceptable salt thereof.
- Embodiment 229. A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 740, or a pharmaceutically acceptable salt thereof.
- Embodiment 230 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 741, or a pharmaceutically acceptable salt thereof.
- Embodiment 23 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 743, or a pharmaceutically acceptable salt thereof.
- Embodiment 232 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 746, or a pharmaceutically acceptable salt thereof.
- Embodiment 233 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 747, or a pharmaceutically acceptable salt thereof.
- Embodiment 23 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 750, or a pharmaceutically acceptable salt thereof.
- Embodiment 235 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 760, or a pharmaceutically acceptable salt thereof.
- Embodiment 236 A synthetic oligonucleotide comprising the sequence of SEQ ID NO: 764, or a pharmaceutically acceptable salt thereof.
- Embodiment 237 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises the synthetic oligonucleotide of any one of embodiments 1-236 and 279-280.
- SNA spherical nucleic acid
- Embodiment 238 A pharmaceutical composition comprising a synthetic oligonucleotide of any one of embodiments 1-236 and 279-280 or a spherical nucleic acid of embodiment 237.
- Embodiment 23 A method of producing alternatively spliced CLN3 RNA in a cell, the method comprising contacting a cell comprising a CLN3 gene and/or a CLN3 gene product with a synthetic oligonucleotide of any one of embodiments 13-236 and 279-280, a spherical nucleic acid of embodiment 237, or a pharmaceutical composition of embodiment 238, to produce alternatively spliced CLN3 RNA in the cell.
- Embodiment 240 A method of producing a CLN3 RNA lacking exon 5 in a cell, the method comprising contacting a cell comprising a CLN3 and/or a CLN3 gene product with a synthetic oligonucleotide comprising the sequence of any one of SEQ ID NO: 11-190, a spherical nucleic acid comprising the synthetic oligonucleotide and a core, or a pharmaceutical composition thereof, to produce CLN3 RNA lacking exon 5 in the cell.
- Embodiment 241 The method of embodiment 240, wherein the synthetic oligonucleotide is a synthetic oligonucleotide of any one of embodiments 13-124.
- Embodiment 242. A method of producing a CLN3 RNA lacking exon 6 in a cell, the method comprising contacting a cell comprising a CLN3 and/or a CLN3 gene product with a synthetic oligonucleotide comprising the sequence of any one of SEQ ID NO: 191-477 and 772, a spherical nucleic acid comprising the synthetic oligonucleotide and a core, or a pharmaceutical composition thereof, to produce CLN3 RNA lacking exon 6 in the cell.
- Embodiment 243 The method of embodiment 242, wherein the synthetic oligonucleotide is a synthetic oligonucleotide of any one of embodiments 125-202 and 279- 280.
- Embodiment 244 A method of producing a CLN3 RNA lacking exon 9 in a cell, the method comprising contacting a cell comprising a CLN3 and/or a CLN3 gene product with a synthetic oligonucleotide comprising the sequence of any one of SEQ ID NO: 478- 771, a spherical nucleic acid comprising the synthetic oligonucleotide and a core, or a pharmaceutical composition thereof, to produce CLN3 RNA lacking exon 9 in the cell.
- Embodiment 245. The method of embodiment 244, wherein the synthetic oligonucleotide is a synthetic oligonucleotide of any one of embodiments 203-236.
- Embodiment 246 A method of ameliorating a symptom of CLN3 Batten disease, wherein the method comprises administering to a subject in need thereof an effective amount of a synthetic oligonucleotide disclosed herein, a spherical nucleic acid (SNA) disclosed herein, or a pharmaceutical composition disclosed herein, in order to ameliorate the symptom of CLN3 Batten disease in the subject.
- a synthetic oligonucleotide disclosed herein
- SNA spherical nucleic acid
- Embodiment 247 The method of embodiment 246, wherein the synthetic oligonucleotide is a synthetic oligonucleotide of any one of embodiments 1-236 and 279-280, the SNA is an SNA of embodiment 237, or the pharmaceutical composition is a pharmaceutical composition of embodiment 238.
- Embodiment 248 The method of embodiment 246 or 247, wherein the symptom of CLN3 Batten disease is visual impairment, retinal degeneration, intellectual disability, impaired cognitive function, speech impairment, seizures, muscle rigidity or stiffness, hypokinesia, stooped posture, arrhythmia, and/or impaired motor function.
- Embodiment 249. A method of administering a synthetic oligonucleotide, a spherical nucleic acid (SNA), or a pharmaceutical composition to a subject, wherein the synthetic oligonucleotide is a synthetic oligonucleotide disclosed herein, the SNA is an SNA disclosed herein, or the pharmaceutical composition is a pharmaceutical composition disclosed herein, wherein the method comprises administering the synthetic oligonucleotide, the SNA, or the pharmaceutical composition to the subject.
- Embodiment 250. The method of embodiment 249, wherein the synthetic oligonucleotide comprises the sequence of any one of SEQ ID NO: 11-772.
- Embodiment 251 The method of embodiment 249, wherein the synthetic oligonucleotide is a synthetic oligonucleotide of any one of embodiments 1-236 and 279-280.
- Embodiment 252 The method of embodiment 249, wherein the SNA is an SNA comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising the sequence of any one of SEQ ID NO: 11-772.
- Embodiment 253 The method of embodiment 249, wherein the SNA is an SNA of embodiment 237.
- Embodiment 254 The method of embodiment 249, wherein the pharmaceutical composition is a pharmaceutical composition of embodiment 238.
- Embodiment 255 The method of any one of embodiments 249-254, wherein the subject is an animal.
- Embodiment 256 The method of any one of embodiments 249-255, wherein the subject is a human.
- Embodiment 257 The method of embodiment 256, wherein the human is a patient having or suspected of having CLN3 Batten disease.
- Embodiment 258 The method of any one of embodiments 249-257, wherein the synthetic oligonucleotide, the SNA, or the pharmaceutical composition is administered to the subject via intrathecal injection, intracistema magna injection, or intravitreal injection.
- Embodiment 259. The method of any one of embodiments 249-258, wherein the synthetic oligonucleotide, the SNA, or the pharmaceutical composition is administered to the central nervous system of the subject.
- Embodiment 260 The method of embodiment 259, wherein the synthetic oligonucleotide, the SNA, or the pharmaceutical composition is administered to one or more regions of the brain of the subject.
- Embodiment 261 The method of embodiment 260, wherein the one or more regions of the brain are the cortex, the cerebellum, the hippocampus, the midbrain, the thalamus, and/or the occipital lobe.
- Embodiment 262 The method of any one of embodiments 249-258, wherein the synthetic oligonucleotide, the SNA, or the pharmaceutical composition is administered to one or more cells of the eye of the subject.
- Embodiment 263. The method of embodiment 262, wherein the one or more cells of the eye are retinal cells.
- Embodiment 264. A method of administering a synthetic oligonucleotide, a spherical nucleic acid (SNA), or a pharmaceutical composition to a subject, wherein the synthetic oligonucleotide is a synthetic oligonucleotide disclosed herein, the SNA is an SNA disclosed herein, or the pharmaceutical composition is a pharmaceutical composition disclosed herein, and wherein the synthetic oligonucleotide, SNA, or pharmaceutical composition is administered via intrathecal or intravitreal injection.
- SNA spherical nucleic acid
- Embodiment 265. Use of a spherical nucleic acid (SNA) in a method of treating a disease or disorder, the SNA comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide disclosed herein.
- SNA spherical nucleic acid
- Embodiment 266 Use of a spherical nucleic acid (SNA) in a method of treating a disease or disorder, the SNA comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises the synthetic oligonucleotide of any one of embodiments 1- 236 and 279-280.
- SNA spherical nucleic acid
- Embodiment 267 A synthetic oligonucleotide for use as a medicament, wherein the synthetic oligonucleotide is a synthetic oligonucleotide disclosed herein.
- Embodiment 268 A synthetic oligonucleotide for use as a medicament, wherein the synthetic oligonucleotide is a synthetic oligonucleotide of any one of embodiments 1-236 and 279-280.
- Embodiment 26 A spherical nucleic acid (SNA) for use as a medicament, wherein the SNA comprises a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide disclosed herein.
- SNA spherical nucleic acid
- Embodiment 270 A spherical nucleic acid (SNA) for use as a medicament, wherein the SNA comprises a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide of any one of embodiments 1-236 and 279-280.
- SNA spherical nucleic acid
- Embodiment 271 A synthetic oligonucleotide for use in treating a disease or disorder, wherein the synthetic oligonucleotide is a synthetic oligonucleotide disclosed herein.
- Embodiment 272 A synthetic oligonucleotide for use in treating a disease or disorder, wherein the synthetic oligonucleotide is a synthetic oligonucleotide of any one of embodiments 1-236 and 279-280.
- Embodiment 273 The synthetic oligonucleotide of embodiment 271 or 272 for use in treating a neurodegenerative disease or disorder.
- Embodiment 274 The synthetic oligonucleotide of embodiment 273, wherein the neurodegenerative disease or disorder is CLN3 Batten disease.
- Embodiment 275 A spherical nucleic acid (SNA) for use in treating a disease or disorder, wherein the SNA comprises a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide disclosed herein.
- SNA spherical nucleic acid
- Embodiment 276 A spherical nucleic acid (SNA) for use in treating a disease or disorder, wherein the SNA comprises a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide of any one of embodiments 1-236 and 279-280.
- SNA spherical nucleic acid
- Embodiment 277 The SNA of embodiment 275 or 276 for use in treating a neurodegenerative disease or disorder.
- Embodiment 278 The SNA of embodiment 277, wherein the neurodegenerative disease or disorder is CLN3 Batten disease.
- Embodiment 279. A synthetic oligonucleotide comprising the structure moeA*moeT*moeG*moeA*moeG*moeA*moeA*moeA*moeA*moeA*moeG*moeG*moeC*moeA *moeA*moeC*moeA*moeG*moeA/iSpl8//iSpl8//3CholTEG/ (Seq ID No: 355), or a pharmaceutically acceptable salt thereof.
- Embodiment 280 A synthetic oligonucleotide comprising the structure /5-Me- moeC/*moeT* moeG*moeA*moeG*moeA*moeG*moeA*moeA* moeG*moeG*/5-Me- moeC/*moeA*moeA* moeC*/5-Me-moeC/* moeA*moeG*moeA*moeA/iSp 18//iSp 18/ /3CholTEG/ (Seq ID No: 772), or a pharmaceutically acceptable salt thereof.
- RNA nucleoside comprising a 2’ -OH sugar moiety and a thymine base
- nucleic acid sequences provided herein 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.
- an oligonucleotide having the nucleobase sequence “ATCGATCG” encompasses any oligonucleotide having such nucleobase sequence, whether modified or unmodified, including, but not limited to, such compounds comprising RNA bases, such as those having sequence “AUCGAUCG” and those having some DNA bases and some RNA bases such as “AUCGATCG” (e.g., wherein each T nucleotide is optionally substituted with a U, and vice versa) and those having other modified nucleobases, such as “AT-moeC-GAUCG,” wherein moeC indicates a cytosine base comprising a sugar moiety with 2’-MOE modification (e.g., wherein each individual nucleotide is optionally chemically modified).
- RNA bases such as those having sequence “AUCGAUCG” and those having some DNA bases and some RNA bases such as “AUCGATCG” (e.g., wherein each T nucleotide is optionally substituted with
- Certain compounds disclosed herein e.g., synthetic oligonucleotides have one or more asymmetric center and thus give rise to enantiomers, diastereomers, and other stereoisomeric configurations that may be defined, in terms of absolute stereochemistry, as (Rp) or (Sp), as alpha or beta such as for sugar anomers, or as (D) or (L), such as for amino acids, etc.
- Compounds provided herein that are drawn or described as having certain stereoisomeric configurations include only the indicated compounds.
- Compounds provided herein that are drawn or described with undefined stereochemistry include all such possible isomers, including their stereorandom and optically pure forms, unless specified otherwise.
- tautomeric forms of the compounds herein are also included unless otherwise indicated.
- the compounds disclosed herein include variations in which one or more atoms are replaced with a non-radioactive isotope or radioactive isotope of the indicated element.
- compounds herein that comprise hydrogen atoms encompass all possible deuterium substitutions for each of the ⁇ hydrogen atoms.
- Isotopic substitutions encompassed by the compounds herein include but are not limited to: 3 ⁇ 4 or 3 H in place of 'H, 13 C or 14 C in place of 12 C, 15 N in place of 14 N, 17 0 or 18 0 in place of 16 0, and 33 S, 34 S, 35 S, or 36 S in place of 32 S.
- non-radioactive isotopic substitutions may impart new properties on the oligomeric compound that are beneficial for use as a therapeutic or research tool.
- radioactive isotopic substitutions may make the compound suitable for research or diagnostic purposes such as imaging.
- CLN3 splicing modulation by SNAs ⁇ Sequence start site indicates the position of the 5’-most nucleotide within SEQ ID NO: 1 to which each oligonucleotide is complementary.
- Genomic locus Homo sapiens CLN3 lysosomal/endosomal transmembrane protein (CLN3)
Abstract
La présente invention concerne des compositions et des méthodes pour le traitement de la maladie de Batten, par exemple par modulation de l'épissage de CLN3. Dans certains modes de réalisation, les compositions consistent en des acides nucléiques sphériques (SNA) ciblant une région d'une séquence CLN3. Dans certains modes de réalisation, les compositions modulent l'épissage de CLN3 et augmentent l'expression de la protéine CLN3 dans une cellule ou un sujet. De telles compositions et méthodes sont utiles, par exemple, dans le traitement, la prévention et/ou la réduction des symptômes et des états liés à la maladie de Batten.
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11633503B2 (en) | 2009-01-08 | 2023-04-25 | Northwestern University | Delivery of oligonucleotide-functionalized nanoparticles |
EP3849564A4 (fr) * | 2018-09-10 | 2023-08-09 | Ionis Pharmaceuticals, Inc. | Composés et méthodes pour moduler l'expression de cln3 |
US11866700B2 (en) | 2016-05-06 | 2024-01-09 | Exicure Operating Company | Liposomal spherical nucleic acid (SNA) constructs presenting antisense oligonucleotides (ASO) for specific knockdown of interleukin 17 receptor mRNA |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015084884A2 (fr) * | 2013-12-02 | 2015-06-11 | Isis Pharmaceuticals, Inc. | Composés antisens et leurs utilisations |
WO2020055917A1 (fr) * | 2018-09-10 | 2020-03-19 | Ionis Pharmaceuticals, Inc. | Composés et méthodes pour moduler l'expression de cln3 |
WO2020118110A1 (fr) * | 2018-12-05 | 2020-06-11 | Fred Hutchinson Cancer Research Center | Fabrication avec manipulation réduite et minimale de cellules génétiquement modifiées |
-
2022
- 2022-01-05 WO PCT/US2022/011291 patent/WO2022150369A1/fr active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015084884A2 (fr) * | 2013-12-02 | 2015-06-11 | Isis Pharmaceuticals, Inc. | Composés antisens et leurs utilisations |
WO2020055917A1 (fr) * | 2018-09-10 | 2020-03-19 | Ionis Pharmaceuticals, Inc. | Composés et méthodes pour moduler l'expression de cln3 |
WO2020118110A1 (fr) * | 2018-12-05 | 2020-06-11 | Fred Hutchinson Cancer Research Center | Fabrication avec manipulation réduite et minimale de cellules génétiquement modifiées |
Non-Patent Citations (3)
Title |
---|
CENTA JL ET AL.: "Therapeutic efficacy of antisense oligonucleotides in mouse models of CLN3 Batten disease", NATURE MEDICINE, vol. 26, no. 9, pages 1444 - 51, XP037241575, DOI: 10.1038/s41591-020-0986-1 * |
CUTLER JI ET AL.: "Spherical nucleic acids", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 134, no. 3, 9 January 2012 (2012-01-09), pages 1376 - 91, XP055251026, DOI: 10.1021/ja209351u * |
KAPADIA CHINTAN H., MELAMED JILIAN R., DAY EMILY S.: "Spherical Nucleic Acid Nanoparticles: Therapeutic Potential", BIODRUGS, ADIS INTERNATIONAL LTD., NZ, vol. 32, no. 4, 1 August 2018 (2018-08-01), NZ , pages 297 - 309, XP055953268, ISSN: 1173-8804, DOI: 10.1007/s40259-018-0290-5 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11633503B2 (en) | 2009-01-08 | 2023-04-25 | Northwestern University | Delivery of oligonucleotide-functionalized nanoparticles |
US11866700B2 (en) | 2016-05-06 | 2024-01-09 | Exicure Operating Company | Liposomal spherical nucleic acid (SNA) constructs presenting antisense oligonucleotides (ASO) for specific knockdown of interleukin 17 receptor mRNA |
EP3849564A4 (fr) * | 2018-09-10 | 2023-08-09 | Ionis Pharmaceuticals, Inc. | Composés et méthodes pour moduler l'expression de cln3 |
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