WO2019157531A1 - Modified compounds and uses thereof - Google Patents

Modified compounds and uses thereof Download PDF

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Publication number
WO2019157531A1
WO2019157531A1 PCT/US2019/017725 US2019017725W WO2019157531A1 WO 2019157531 A1 WO2019157531 A1 WO 2019157531A1 US 2019017725 W US2019017725 W US 2019017725W WO 2019157531 A1 WO2019157531 A1 WO 2019157531A1
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Prior art keywords
oligomeric compound
sugar moiety
modified
central region
nucleoside
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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PCT/US2019/017725
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English (en)
French (fr)
Inventor
Punit Seth
Michael OESTERGAARD
Michael T. Migawa
Xue-Hai Liang
Wen SHEN
Stanley T. Crooke
Eric E. Swayze
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Ionis Pharmaceuticals Inc
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Ionis Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority to JP2020542860A priority Critical patent/JP7317029B2/ja
Priority to EP19751124.9A priority patent/EP3752612A4/en
Priority to AU2019218987A priority patent/AU2019218987B2/en
Priority to CA3090901A priority patent/CA3090901A1/en
Priority to US16/968,701 priority patent/US11332733B2/en
Application filed by Ionis Pharmaceuticals Inc filed Critical Ionis Pharmaceuticals Inc
Publication of WO2019157531A1 publication Critical patent/WO2019157531A1/en
Priority to PCT/US2019/054848 priority patent/WO2020072991A1/en
Priority to EP19868336.9A priority patent/EP3861118A4/en
Priority to US17/282,335 priority patent/US20220064636A1/en
Anticipated expiration legal-status Critical
Priority to US17/172,333 priority patent/US11149264B2/en
Priority to US17/697,577 priority patent/US12234447B2/en
Priority to US18/984,293 priority patent/US20250354135A1/en
Ceased legal-status Critical Current

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Definitions

  • the present disclosure provides oligomeric compounds comprising a modified oligonucleotide having a central region comprising one or more modifications.
  • the present disclosure provides oligomeric compounds having an improved therapeutic index or an increased maximum tolerated dose.
  • RNAi refers to antisense -mediated gene silencing through a mechanism that utilizes the RNA -induced silencing complex (RISC).
  • RNA target function is by an occupancy-based mechanism such as is employed naturally by microRNA.
  • MicroRNAs are small non-coding RNAs that regulate the expression of protein coding RNAs. The binding of an antisense compound to a microRNA prevents that microRNA from binding to its messenger RNA targets, and thus interferes with the function of the microRNA. MicroRNA mimics can enhance native microRNA function. Certain antisense compounds alter splicing of pre-mRNA.
  • sequence-specificity makes antisense compounds attractive as tools for target validation and gene functionalization, as well as therapeutics to selectively modulate the expression of genes involved in the pathogenesis of disease.
  • Antisense technology is an effective means for modulating the expression of one or more specific gene products and can therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications.
  • Chemically modified nucleosides may be incorporated into antisense compounds to enhance one or more properties, such as nuclease resistance, pharmacokinetics, or affinity for a target nucleic acid. Summary
  • the present disclosure provides oligomeric compounds and methods of using oligomeric compounds that comprise a modified oligonucleotide consisting of 14-23 linked nucleosides, wherein the modified oligonucleotide comprises a gapmer consisting of a 5’-region, a central region, and a 3’ - region wherein: the 5’-region consists of 2-5 linked modified nucleosides, wherein each nucleoside of the 5’-region comprises a 2’-modified f iranosyl sugar moiety;
  • the 3’-region consists of 1-5 linked modified nucleosides, wherein each nucleoside of the 3’-region comprises a 2’-modified fiiranosyl sugar moiety;
  • the central region consists of 7-10 linked nucleosides, where each nucleoside of the central region comprises a sugar moiety selected from an unmodified 2’- -D-deoxyribosyl sugar moiety and a modified sugar moiety;
  • the 3’- and 5’-most nucleosides of the central region each comprise a sugar moiety independently selected from a 2’-deoxyfiiranosyl sugar moiety or a sugar surrogate; and wherein
  • the central region comprises:
  • At least one altered nucleotide comprising a modified intemucleoside linkage other than phosphorothioate and/or a modified nucleobase other than 5-methylcytosine and/or a modified sugar moiety;
  • nucleosides each comprising an unmodified 2’- -D-deoxyribosyl sugar moiety.
  • oligomeric compounds are provided comprising a single conjugate group linked to the 5’-end. In certain embodiments, oligomeric compounds are provided comprising a single conjugate group linked to the 3’-end.
  • the oligomeric compounds provided herein have an increased maximum tolerated dose when administered to an animal compared to an otherwise identical oligomeric compound except that the otherwise identical oligomeric compound lacks the altered nucleotide in the central region.
  • the oligomeric compounds provided herein have an increased therapeutic index compared to an otherwise identical oligomeric compound except that the otherwise identical oligomeric compound lacks the alterered nucleotide in the central region.
  • methods of inhibiting target RNA comprising contacting one or more cells, a tissue or an animal with an oligomeric compound as provided herein wherein said oligomeric compound is complementary to a target RNA.
  • the cells are in a human.
  • the target RNA is human RNA.
  • the target is human mRNA.
  • the target RNA is cleaved, thereby inhibiting its function.
  • in vitro methods of inhibiting gene expression comprising contacting one or more cells or a tissue with an oligomeric compound as provided herein.
  • oligomeric compounds are provided for use in an in vivo method of inhibiting gene expression wherein the method comprises contacting one or more cells, a tissue or an animal with an oligomeric compound as provided herein.
  • oligomeric compounds are provided for use in medical therapy.
  • Figure 1 is a SDS-PAGE gel showing the proteins eluted from a biotin-capture experiment with increasing concentrations of unlabeled modified oligonucleotides 508031, 895154, 895155, and 895156.
  • Figure 2 is a SDS-PAGE gel showing the proteins eluted from a biotin-capture experiment with decreasing concentrations of unlabeled modified oligonucleotides 464917, 465977, 483706, and 820685.
  • Figure 2B shows aligned western blots for a variety of proteins at decreasing elution concentrations of 464917, 465977, 483706, and 820685.
  • Figure 3 is a SDS-PAGE gel showing the proteins eluted from a biotin-capture experiment with decreasing concentrations of unlabeled modified oligonucleotides 464917, 465178, 464932, and 465131.
  • Figure 4 is a SDS-PAGE gel showing the proteins eluted from a biotin-capture experiment with unlabeled modified oligonucleotides containing 2x MOP linkages in the central region.
  • Figure 5A is a SDS-PAGE gel showing proteins eluted from biotin-capture experiments with unlabled modified oligonucleotides 464917 and 549148.
  • Figure 5B shows aligned western blots for a variety of proteins at increasing elution concentrations of 464917 and 549148.
  • RNA or“DNA” intemucleoside linkage, or a nucleobase.
  • an oligonucleotide comprising a nucleoside comprising a 2’-OH(H) sugar moiety and a thymine base could be described as a DNA having a modified sugar (2’-OH in place of one 2’-H of DNA) or as an RNA having a modified base (thymine (methylated uracil) in place of an uracil of RNA).
  • nucleic acid sequences provided herein, including, but not limited to those in the sequence listing are intended to encompass nucleic acids containing any combination of natural or modified RNA and/or DNA, including, but not limited to such nucleic acids having modified nucleobases.
  • an oligomeric compound having the nucleobase sequence“ATCGATCG” encompasses any oligomeric compounds 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” and oligomeric compounds having other modified nucleobases, such as“AT m CGAUCG,” wherein '"C indicates a cytosine base comprising a methyl group at the 5-position.
  • “2’-deoxyfuranosyl sugar moiety” or“2’-deoxyfuranosyl sugar” means a furanosyl sugar moiety having two hydrogens at the 2’ -position.
  • 2’-deoxyfuranosyl sugar moieties may be unmodified or modified and may be substituted at positions other than the 2’-position or unsubstituted.
  • a b-0-2’- deoxyribosyl sugar moiety or 2’ ⁇ -D-deoxyribosyl sugar moiety in the context of an oligonucleotide is an unsubstituted, unmodified 2’-deoxyfuranosyl and is found in naturally occurring deoxyribonucleic acids (DNA).
  • furanosyl sugar moiety comprises a substituent other than H or OH at the 2’- position of the furanosyl sugar moiety.
  • 2’-modified furanosyl sugar moieties include non-bicyclic and bicyclic sugar moieties and may comprise, but are not required to comprise, additional substituents at other positions of the furanosyl sugar moiety.
  • “2’-substituted” in reference to a furanosyl sugar moiety or nucleoside comprising a furanosyl sugar moiety means the furanosyl sugar moiety or nucleoside comprising the furanosyl sugar moiety comprises a substituent other than H or OH at the 2’-position and is a non-bicyclic furanosyl sugar moiety.
  • 2’- substituted furanosyl sugar moieties do not comprise additional substituents at other positions of the furanosyl sugar moiety other than a nucleobase and/or intemucleoside linkage(s) when in the context of an oligonucleotide.
  • furanosyl sugar moiety comprises a substituent other than H at the 4’-position of the furanosyl sugar moiety.
  • 4’-modified furanosyl sugar moieties include non-bicyclic and bicyclic sugar moieties and may but are not required to comprise additional substituents at other positions of the furanosyl sugar moiety.
  • “4’-substituted” in reference to a furanosyl sugar moiety or nucleoside comprising a furanosyl sugar moiety means the furanosyl sugar moiety or nucleoside comprising the furanosyl sugar moiety comprises a substituent other than H at the 4’-position and is a non-bicyclic furanosyl sugar moiety. 4’- substituted furanosyl sugar moieties do not comprise additional substituents at other positions of the furanosyl sugar moiety other than a nucleobase and/or intemucleoside linkage(s) when in the context of an oligonucleotide.
  • “5’-modified” in reference to a furanosyl sugar moiety or nucleoside comprising a furanosyl sugar moiety means the furanosyl sugar moiety comprises a substituent other than H at the 5’-position of the furanosyl sugar moiety.
  • 5’-modified furanosyl sugar moieties may but are not required to comprise additional substituents at other positions of the furanosyl sugar moiety.
  • “5’-substituted” in reference to a furanosyl sugar moiety or nucleoside comprising a furanosyl sugar moiety means the furanosyl sugar moiety or nucleoside comprising the furanosyl sugar moiety comprises a substituent other than H at the 5’-position and is a non-bicyclic furanosyl sugar moiety.
  • 5’- substituted furanosyl sugar moieties do not comprise additional substituents at other positions of the furanosyl sugar moiety other than a nucleobase and/or intemucleoside linkage(s) when in the context of an oligonucleotide.
  • administering refers to routes of introducing a compound or composition provided herein to a subject to perform its intended function.
  • routes of administration include, but are not limited to, administration by inhalation, subcutaneous injection, intrathecal injection, and oral administration.
  • “administered concomitantly” or“co-administration” means administration of two or more compounds in any manner in which the pharmacological effects of both are manifest in the patient. Concomitant administration does not require that both compounds be administered in a single pharmaceutical composition, in the same dosage form, by the same route of administration, or at the same time. The effects of both compounds need not manifest themselves at the same time. The effects need only be overlapping for a period of time and need not be coextensive. Concomitant administration or co-administration encompasses administration in parallel, sequentially, separate, or simultaneous administration.
  • “ALT” means alanine aminotransferase.
  • “AST” means aspartate transaminase.
  • plasma levels of ALT and AST in a subject are measured in units per liter.
  • “units per liter” in the context of plasma ALT or plasma AST levels means international units per liter, the standard units for measurement of plasma ALT or plasma AST levels used by those of ordinary skill in the medical arts.
  • animal refers to a human or non-human animal, including, but not limited to, mice, rats, rabbits, dogs, cats, pigs, and non-human primates, including, but not limited to, monkeys and chimpanzees.
  • antisense activity means any detectable and/or measurable change attributable to the hybridization of an antisense compound to its target nucleic acid.
  • antisense activity is a decrease in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid compared to target nucleic acid levels or target protein levels in the absence of the antisense compound.
  • antisense compound means a compound comprising an antisense oligonucleotide and optionally one or more additional features, such as a conjugate group or terminal group.
  • antisense oligonucleotide means an oligonucleotide having a nucleobase sequence that is at least partially complementary to a target nucleic acid.
  • “ameliorate” in reference to a treatment means improvement in at least one symptom relative to the same symptom in the absence of the treatment.
  • amelioration is the reduction in the severity or frequency of a symptom or the delayed onset or slowing of progression in the severity or frequency of a symptom.
  • “bicyclic nucleoside” or“BNA” means a nucleoside comprising a bicyclic sugar moiety.
  • “bicyclic sugar” or“bicyclic sugar moiety” means 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 is a modified furanosyl sugar moiety.
  • the bicyclic sugar moiety does not comprise a furanosyl moiety.
  • a“central nervous system target” is a target R A that is expressed in the central nervous system.
  • “cEt” or“constrained ethyl” means a bicyclic sugar moiety, wherein the first ring of the bicyclic sugar moiety is a ribosyl sugar moiety, the second ring of the bicyclic sugar is formed via a bridge connecting the 4’-carbon and the 2’-carbon, the bridge has the formula 4'-CH(CH 3 )-0-2', and the methyl group of the bridge is in the S configuration.
  • a cEt bicyclic sugar moiety is in the b-D configuration.
  • a“cEt nucleoside” or“cEt nucleotide” is a nucleoside or nucleotide comprising a cEt.
  • “complementary” in reference to an oligonucleotide means that at least 70% of the nucleobases of such 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 are nucleobase pairs 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 (C) and guanine (G), 5 -methyl cytosine (“C) and guanine (G).
  • Complementary oligonucleotides and/or nucleic acids need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated. As used herein, “fully complementary” or “100% complementary” in reference to oligonucleotides means that such oligonucleotides are complementary to another oligonucleotide or nucleic acid at each nucleoside of the oligonucleotide.
  • conjugate group means a group of atoms that is directly or indirectly attached to an oligonucleotide.
  • Conjugate groups may comprise a conjugate moiety and a conjugate linker that attaches the conjugate moiety to the oligonucleotide.
  • conjugate linker means a group of atoms comprising at least one bond that connects a conjugate moiety to an oligonucleotide.
  • conjugate moiety means a group of atoms that is attached to an oligonucleotide via a conjugate linker.
  • oligonucleotide refers to nucleosides, nucleobases, sugar moieties, or intemucleoside linkages that are immediately adjacent to each other independent of the other moieties of the oligonucleotide.
  • “contiguous nucleobases” means nucleobases that are immediately adjacent to each other in a sequence.
  • Moieties that are“directly linked” are immediately adjacent to each other and not separated by any other type of moiety.
  • cytotoxic or“cytotoxicity” in the context of an effect of an oligomeric compound or a parent oligomeric compound on cultured cells means an at least 2-fold increase in caspase activation following administration of 10 mM or less of the oligomeric compound or parent oligomeric compound to the cultured cells relative to cells cultured under the same conditions but that are not administered the oligomeric compound or parent oligomeric compound.
  • cytotoxicity is measured using a standard in vitro cytotoxicity assay.
  • double-stranded antisense compound means an antisense compound comprising two oligomeric compounds that are complementary to each other and form a duplex, and wherein one of the two said oligomeric compounds comprises an antisense oligonucleotide.
  • an effective amount means the amount of compound sufficient to effectuate a desired physiological outcome in a subject in need of the compound.
  • the effective amount may vary among subjects depending on the health and physical condition of the subject to be treated, the taxonomic group of the subjects to be treated, the formulation of the composition, assessment of the subject’s medical condition, and other relevant factors.
  • “efficacy” means the ability to produce a desired effect.
  • “expression” includes all the functions by which a gene’s coded information is converted into structures present and operating in a cell. Such structures include, but are not limited to, the products of transcription and translation.
  • “modulation of expression” means any change in amount or activity of a product of transcription or translation of a gene. Such a change may be an increase or a reduction of any amount relative to the expression level prior to the modulation.
  • “gapmer” means an oligonucleotide having a central region comprising a plurality of nucleosides that support RNase H cleavage positioned between a 5’-region and a 3’-region.
  • the nucleosides of the 5’-region and 3’-region each comprise a 2’-modified furanosyl sugar moiety
  • the 3’- and 5’-most nucleosides of the central region each comprise a sugar moiety independently selected from a 2’- deoxyfuranosyl sugar moiety or a sugar surrogate.
  • the positions of the central region refer to the order of the nucleosides of the central region and are counted starting from the 5’-end of the central region.
  • the 5’- most nucleoside of the central region is at position 1 of the central region.
  • The“central region” may be referred to as a“gap”, and the“5’-region” and“3’-region” may be referred to as“wings”.
  • hepatotoxic in the context of a mouse means a plasma ALT level that is above 300 units per liter. Hepatotoxicity of an oligomeric compound or parent oligomeric compound that is
  • administered to a mouse is determined by measuring the plasma ALT level of the mouse 24 hours to 2 weeks following at least one dose of 1-150 mg/kg of the compound.
  • hepatotoxic in the context of a human means a plasma ALT level that is above 150 units per liter. Hepatotoxicity of an oligomeric compound or parent oligomeric compound that is
  • administered to a human is determined by measuring the plasma ALT level of the human 24 hours to 2 weeks following at least one dose of 10-300 mg of the compound.
  • 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.
  • inhibiting the expression or activity refers to a reduction or blockade of the expression or activity relative to the expression or activity in an untreated or control sample and does not necessarily indicate a total elimination of expression or activity.
  • intemucleoside linkage means a group or bond that forms a covalent linkage between adjacent nucleosides in an oligonucleotide.
  • modified intemucleoside linkage means any intemucleoside linkage other than a naturally occurring, phosphodiester intemucleoside linkage.
  • Phosphorothioate linkage means a modified intemucleoside linkage in which one of the non-bridging oxygen atoms of a phosphodiester is replaced with a sulfur atom. Modified intemucleoside linkages may or may not contain a phosphoms atom.
  • abasic nucleoside means a sugar moiety in an oligonucleotide or oligomeric compound that is not directly connected to a nucleobase.
  • an abasic nucleoside is adjacent to one or two nucleosides in an oligonucleotide.
  • LICA-l is a conjugate group that is represented by the formula:
  • linker-nucleoside means a nucleoside that links, either directly or indirectly, an oligonucleotide to a conjugate moiety. Linker-nucleosides are located within the conjugate linker of an oligomeric compound. Linker-nucleosides are not considered part of the oligonucleotide portion of an oligomeric compound even if they are contiguous with the oligonucleotide.
  • non-bicyclic sugar or“non-bicyclic sugar moiety” means a sugar moiety that comprises fewer than 2 rings. Substituents of modified, non-bicyclic sugar moieties do not form a bridge between two atoms of the sugar moiety to form a second ring.
  • “linked nucleosides” are nucleosides that are connected in a continuous sequence (i.e. no additional nucleosides are present between those that are linked).
  • liver target is a target RNA expressed in the liver wherein modulation of the expression of the target RNA in the liver is desired for therapeutic benefit.
  • a liver target is expressed in tissues other than the liver as well as in the liver.
  • modulation of the expression of a target RNA that is“not a liver target” is desired in a tissue that is not the liver for therapeutic benefit.
  • a target RNA that is not a liver target is expressed in the liver and is modulated by an oligomeric compound in therapy.
  • 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 when the first and second oligomeric compound are aligned.
  • “modulating” refers to changing or adjusting a feature in a cell, tissue, organ or organism.
  • “MOE” means methoxyethyl.
  • 2’-MOE” or“2’-0-methoxyethyl” means a 2’- OCH2CH2OCH3 group at the 2’-position of a furanosyl ring.
  • the 2’-0CH 2 CH 2 0CH 3 group is in place of the 2’-OH group of a ribosyl ring or in place of a 2’-H in a 2’-deoxyribosyl ring.
  • “MOP” or“methoxypropyl intemucleoside linkage” means the alkyl phosphonate intemucleoside bond shown below:
  • motif means the pattern of unmodified and/or modified sugar moieties, nucleobases, and/or intemucleoside linkages, in an oligonucleotide.
  • nucleobase means 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 capable of pairing with at least one unmodified nucleobase.
  • a universal base is a nucleobase that can pair with any one of the five unmodified nucleobases.
  • 5- methylcytosine ( m C) is one example of a modified nucleobase.
  • nucleobase sequence means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar moiety or intemucleoside linkage modification.
  • nucleoside means a moiety comprising a nucleobase and a sugar moiety.
  • the nucleobase and sugar moiety are each, independently, unmodified or modified.
  • modified nucleoside means a nucleoside comprising a modified nucleobase and/or a modified sugar moiety.
  • oligomeric compound means a compound consisting of an oligonucleotide and optionally one or more additional features, such as a conjugate group or terminal group.
  • oligonucleotide means a strand of linked nucleosides connected via intemucleoside linkages, wherein each nucleoside and intemucleoside linkage may be modified or unmodified. Unless otherwise indicated, oligonucleotides consist of 8-50 linked nucleosides.
  • modified oligonucleotide means an oligonucleotide, wherein at least one nucleoside or intemucleoside linkage is modified.
  • “unmodified oligonucleotide” means an oligonucleotide that does not comprise any nucleoside modifications or intemucleoside modifications.
  • parent oligomeric compound in the context of an oligomeric compound comprising at least one modification in the central region other than phosphorothioate or 5-methylcytosine means an oligomeric compound that is identical to the oligomeric compound comprising the at least one modification in the central region except that the parent oligomeric compound does not comprise at least one modified intemucleoside linkage other than phosphorothioate and/or at least one modified nucleoside comprising a modified nucleobase other than 5-methylcytosine and/or a modified sugar moiety.
  • a parent oligomeric compound and its counterpart oligomeric compound comprising at least one modification in the central region have identical nucleobase sequences or differ in nucleobase sequence only due to inclusion of a modified nucleobase other than 5-methylcytosine in the oligomeric compound comprising at least one modification in the central region.
  • “pharmaceutically acceptable carrier or diluent” means any substance suitable for use in administering to an animal. Certain such carriers enable pharmaceutical compositions to be formulated as, for example, liquids, powders, or suspensions that can be aerosolized or otherwise dispersed for inhalation by a subject.
  • a pharmaceutically acceptable carrier or diluent is sterile water; sterile saline; or sterile buffer solution.
  • pharmaceutically acceptable salts means physiologically and pharmaceutically acceptable salts of compounds, such as oligomeric compounds, i.e., salts that retain the desired biological activity of the compound and do not impart undesired toxicological effects thereto.
  • a pharmaceutical composition means a mixture of substances suitable for administering to a subject.
  • a pharmaceutical composition may comprise an antisense compound and an aqueous solution.
  • RNAi compound means an antisense compound that acts, at least in part, through RISC or Ago2 to modulate a target nucleic acid and/or protein encoded by a target nucleic acid.
  • RNAi compounds include, but are not limited to double-stranded siRNA, single-stranded RNA (ssRNA), and microRNA, including microRNA mimics.
  • an RNAi compound modulates the amount, activity, and/or splicing of atarget nucleic acid.
  • the term RNAi compound excludes antisense oligonucleotides that act through RNase H.
  • the term“single -stranded” in reference to an antisense compound means such a compound consisting of one oligomeric compound that is not paired with a second oligomeric compound to form a duplex.“Self-complementary” in reference to an oligonucleotide means an oligonucleotide that at least partially hybridizes to itself.
  • a compound consisting of one oligomeric compound, wherein the oligonucleotide of the oligomeric compound is self-complementary is a single-stranded compound.
  • a single-stranded antisense or oligomeric compound may be capable of binding to a complementary oligomeric compound to form a duplex, in which case the compound would no longer be single-stranded.
  • standard cell assay means any of the assays described in Examples 1-9, and reasonable variations thereof.
  • standard in vitro activity assay means a procedure, as described in Example 1 herein, wherein expression is measured by RT-PCR in cultured cells expressing the target RNA following administration of an oligomeric compound to the cultured cells.
  • standard in vitro cytotoxicity assay means a procedure, as described in Example 8 herein, wherein activation of caspases 3 and 7 is measured in cultured 3T3-L1 cells following administration of an oligomeric compound to the cells.
  • stereochemical configuration of a chiral center is considered random when it is the result of a synthetic method that is not designed to control the stereochemical configuration.
  • subject means a human or non-human animal selected for treatment or therapy.
  • “sugar moiety” means an unmodified sugar moiety or a modified sugar moiety.
  • “unmodified sugar moiety” means a b-D-ribosyl moiety, as found in naturally occurring RNA, or a -D-2’-deoxyribosyl sugar moiety as found in naturally occurring DNA.
  • “modified sugar moiety” or“modified sugar” means a sugar surrogate or a furanosyl sugar moiety other than a b-D-ribosyl or a b-D-2’-deoxyribosyl.
  • Modified furanosyl sugar moieties may be modified or substituted at a certain position(s) of the sugar moiety, or unsubstituted, and they may or may not have a stereoconfiguration other than b-D- ribosyl.
  • Modified furanosyl sugar moieties include bicyclic sugars and non-bicyclic sugars.
  • sugar surrogate means a modified sugar moiety that does not comprise a furanosyl or tetrahydrofuranyl ring (is not a“furanosyl sugar moiety”) and 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 nucleic acids.
  • “susceptible” in the context of a disease, disorder, condition, or symptom such as degeneration, damage, or elevated apoptosis means that a subject has a higher risk than the average risk for the general population for the disease, disorder, condition, or symptom.
  • target nucleic acid means a nucleic acid that an oligomeric compound, such as an antisense compound, is designed to affect.
  • an oligomeric compound comprises an oligonucleotide having a nucleobase sequence that is complementary to more than one RNA, only one of which is the target RNA of the oligomeric compound.
  • the target RNA is an RNA present in the species to which an oligomeric compound is administered.
  • a“liver target” is a target RNA that is expressed in the liver, and modulation of expression of the target RNA in the liver provides a therapeutic effect.
  • a“central nervous system target” is a target RNA that is expressed in the central nervous system, and modulation of expression of the target RNA in the central nervous system provides a therapeutic effect.
  • the present disclosure provides certain individual cellular, tissue, or organ targets.
  • modulation of the expression of the target RNA in the individual cellular, tissue, or organ target is desired for therapeutic benefit.
  • modulation of the target RNA in an individual cellular, tissue, or organ target provides a therapeutic effect.
  • a cellular, tissue, or organ target is expressed in tissues other than in a particular type of cell, tissue, or organ as well as being expressed in a particular type of cell, tissue, or organ.
  • certain target RNAs may be expressed in both a macrophage and a hepatocyte.
  • “therapeutically effective amount” means an amount of a compound, pharmaceutical agent, or composition that provides a therapeutic benefit to a subject.
  • “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.
  • maximum tolerated dose means the highest dose of a compound that does not cause unacceptable side effects.
  • the maximum tolerated dose is the highest dose of a modified oligonucleotide that does not cause an ALT elevation of three times the upper limit of normal as measured by a standard assay, e.g. the assay of Example 12 or Example 1.
  • the maximum tolerated dose is the highest dose of a modified oligonucleotide that does not cause caspase elevation of greater than 30,000 RLU as measured by a standard assay, e.g. the assay of Example 13,
  • Example 8 Example 8
  • “DNA isomer” means a nucleoside that comprises a modified sugar moiety that is a stereoisomer of -D-2’-deoxyribosyl. As used herein, a“DNA isomer” does not include -D-2’-deoxyribosyl nucleosides.
  • a DNA isomer is 2’-a-D-deoxyribosyl, 2’-a-L-deoxyribosyl, 2’ ⁇ -L-deoxyribosyl, or 2 , -b-0- deoxyxylosyl sugar moiety.
  • “DNA isomer” does not include any nonfuranosyl sugar moieties.
  • “DNA nucleoside” means a nucleoside comprising a 2’-H(H) b-D-2’-deoxyribosyl sugar moiety, as found in naturally-occuring DNA.
  • A“DNA nucleoside” may comprise a modified nucleobase or a uracil nucleobase.
  • a DNA nucleoside may be linked to adjacent nucleosides through unmodified phosphodiester intemucleoside linkages or through modified intemucleoside linkages.
  • a“2’-modified DNA isomer” means a nucleoside that comprises a modified sugar moiety that is selected from 2’ ⁇ -D-deoxyxylosyl (b-D-XNA), 2’-a-D-deoxyribosyl (a-D-DNA), 2’-a-L- deoxyribosyl (a-L-DNA), 2’ ⁇ -L-deoxyribosyl (b-L-DNA), 2’-a-D-deoxyxylosyl (a-L-XNA), 1, 2’-a-L- deoxyxylosyl (a-L-XNA), 2’ ⁇ -L-deoxyxylosyl (b-L-XNA), and that further comprises a 2’-substituent.
  • the 2’-substituent is fluoro, alkoxy, or Ci-Cio alkyl.
  • DNA mimic means a nucleoside other than a DNA nucleoside wherein the nucleobase is directly linked to a carbon atom of a ring bound to a second carbon atom within the ring, wherein the second carbon atom comprises a bond to at least one hydrogen atom, wherein the nucleobase and at least one hydrogen atom are trans to one another relative to the bond between the two carbon atoms.
  • a DNA mimic comprises a structure represented by the formula:
  • Bx is a heterocylic base moiety
  • the ring contains 5-7 members, and the ring is attached at two positions to a hydroxyl, a phosphate, an intemucleoside linking group, or a conjugate linker.
  • a“standard RNase H cleavage assay” is an assay wherein a heteroduplex of the modified oligonucleotide and a complementary strand of unmodified RNA are incubated with each other to form a heteroduplex, and are then incubated with RNase Hl for specified time points before being analyzed on a polyacrylamide gel.
  • a modified nucleoside “supports RNase H cleavage” when incorporated into an oligonucleotide if RNase H cleavage of the complementary RNA is observed within two nucleobases of the modified nucleoside in a standard RNase H cleavage assay.
  • therapeutic index means a comparison of the amount of a compound that causes a therapeutic effect to the amount that causes toxicity.
  • Compounds having a high therapeutic index have strong efficacy and low toxicity.
  • increasing the therapeutic index of a compound increases the amount of the compound that can be safely administered.
  • therapeutic index is the ratio of the amount of modulation of a target nucleic acid by a modified oligonucleotide compared to ALT elevation, wherein the ALT elevation is measured by a standard assay, e.g. the assay of Example 12 or Example 1.
  • therapeutic index is the ratio of the amount of modulation of a target nucleic acid by a modified oligonucleotide compared to caspase elevation, wherein the caspase elevation is measured by a standard assay, e.g. the assay of Example 13, Example 8, or Example 4.
  • an“altered nucleotide” is a nucleotide that comprises one or more modifications relative to a nucleotide comprising a 2’ ⁇ -D-deoxyribosyl sugar moiety, a nucleobase selected from adenine (A), thymine (T), cytosine (C), 5-methyl cytosine (“C), uracil (U), or guanine (G), and a 5’ to 3’ intemucleoside linkage selected from phosphodiester or stereorandom phosphorothioate.
  • the altered nucleotide is an altered nucleoside attached to a phosphorothioate or phosphodiester intemucleoside linkage.
  • the altered nucleotide comprises a 2’ -modified sugar moiety, or is a“2’ -altered nucleotide”.
  • the altered nucleotide comprises a modified intemucleoside linking group, and is a“linkage-altered nucleotide”.
  • a linkage -altered nucleotide comprises an intemucleoside linking group other than phosphodiester or phosphorothioate attached to the 3’ carbon of the sugar moiety, or the equivalent position for a sugar surrogate.
  • the nucleotide on the 5’-end of an intemucleoside linking group other than phosphodiester or phoshporothioate is not an“altered nucleotide”, as used herein.
  • An oligomeric compound comprising a modified oligonucleotide consisting of 14-23 linked nucleosides, wherein the modified oligonucleotide comprises a gapmer consisting of a 5’-region, a central region, and a 3’ - region wherein:
  • the 5’-region consists of 2-5 linked modified nucleosides, wherein each nucleoside of the 5’-region comprises a 2’-modified furanosyl sugar moiety;
  • the 3’-region consists of 1-5 linked modified nucleosides, wherein each nucleoside of the 3’-region comprises a 2’-modified furanosyl sugar moiety;
  • the central region consists of 7-10 linked nucleosides, where each nucleoside of the central region comprises a sugar moiety selected from an unmodified 2’- -D-deoxyribosyl sugar moiety and a modified sugar moiety;
  • the 3’- and 5’-most nucleosides of the central region each comprise a sugar moiety independently selected from a 2’-deoxyfuranosyl sugar moiety or a sugar surrogate; and wherein
  • the central region comprises:
  • nucleosides each comprising an unmodified 2’- -D-deoxyribosyl sugar moiety.
  • oligomeric compound of any of embodiments 1-7 wherein at least one nucleoside of the 5’-region comprises a bicyclic furanosyl sugar moiety.
  • each nucleoside of the 5’-region comprises a bicyclic furanosyl sugar moiety.
  • oligomeric compound of any of embodiments 1-8 wherein at least one nucleoside of the 5’-region comprises a non-bicyclic sugar moiety.
  • oligomeric compound of embodiment 10 wherein the non-bicyclic sugar moiety of the at least one nucleoside of the 5’-region is a 2’ -substituted ribosyl sugar moiety.
  • each nucleoside of the 5’-region comprises a non-bicyclic sugar moiety.
  • each nucleoside of the 5’-region comprises a 2’- substituted ribosyl sugar moiety.
  • each nucleoside of the 5’-region comprises a 2’-modified furanosyl sugar moiety independently selected from a bicyclic sugar moiety and a non-bicyclic sugar moiety, 2’-substituted ribosyl sugar moiety.
  • each bicyclic sugar moiety of the 5’-region is selected from among cEt, LNA, and ENA.
  • each nonbicyclic sugar moiety of the 5’-region has a 2’-substituent selected from among 2’-MOE, 2’-OMe, and 2’-NMA.
  • each nucleobase of the 5’-region is independently selected from among thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.
  • each intemucleoside linkage of the 5’- region is selected from among phosphodiester and phosophorothioate intemucleoside linkages.
  • each nucleoside of the 3’-region comprises a bicyclic furanosyl sugar moiety.
  • each nucleoside of the 3’-region comprises a non-bicyclic sugar moiety.
  • each nucleoside of the 3’-region comprises a 2’- substituted ribosyl sugar moiety.
  • each nucleoside of the 3’-region comprises a 2’-modified furanosyl sugar moiety independently selected from a bicyclic sugar moiety and a non-bicyclic sugar moiety, 2’-substituted ribosyl sugar moiety.
  • each bicyclic sugar moiety of the 3’-region is selected from among cEt, LNA, and ENA.
  • each nonbicyclic sugar moiety of the 3’-region has a 2’-substituent selected from among 2’-MOE, 2’-OMe, and 2’-NMA.
  • each nucleobase of the 3’-region is independently selected from among thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.
  • each intemucleoside linkage of the 3’- region is selected from among phosphodiester and phosophorothioate intemucleoside linkages.
  • each intemucleoside linkage within the central region is selected from among phosphodiester and phosophorothioate intemucleoside linkages.
  • each nucleobase of the central region is independently selected from among thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.
  • intemucleoside linkages other than phosphorothioate is a neutral intemucleoside linkage.
  • oligomeric compound of any of embodiments 1-51 or 53-59 wherein the central region comprises one, and no more than one, modified nucleobase other than 5-methylcytosine.
  • 61. The oligomeric compound of any of embodiments 1-60, wherein each of the unmodified sugar moieties of the central region are 2’- -D-deoxyribosyl sugar moieties.
  • oligomeric compound of any of embodiments 50-66, wherein the one modified sugar moiety of the central region is a sugar surrogate, a bicyclic furanosyl sugar moiety, a non-bicyclic 2’-modified furanosyl sugar moiety, a non-bicyclic 4’-modified furanosyl sugar moiety, a non-bicyclic 5’-modified furanosyl sugar moiety, or a modified 2’-deoxyfuranosyl sugar moiety.
  • oligomeric compound of embodiment 67 wherein the one modified sugar moiety of the central region is a bicyclic ribosyl sugar moiety, a non-bicyclic 2’-modified ribosyl sugar moiety, a non-bicyclic 4’- modified 2’-deoxyribosyl sugar moiety, a non-bicyclic 5’-modified 2’-deoxyribosyl sugar moiety, or a modified 2’-deoxyfuranosyl sugar moiety.
  • the one modified sugar moiety of the central region is a bicyclic ribosyl sugar moiety, a non-bicyclic 2’-modified ribosyl sugar moiety, a non-bicyclic 4’- modified 2’-deoxyribosyl sugar moiety, a non-bicyclic 5’-modified 2’-deoxyribosyl sugar moiety, or a modified 2’-deoxyfuranosyl sugar moiety.
  • oligomeric compound of embodiment 68 wherein the one modified sugar moiety of the central region is a bicyclic ribosyl sugar moiety, a non-bicyclic 2’-substituted ribosyl sugar moiety, a non-bicyclic 4’- substituted 2’-deoxyribosyl sugar moiety, a non-bicyclic 5’-substituted 2’-deoxyribosyl sugar moiety, or a modified, unsubstituted 2’-deoxyfuranosyl sugar moiety.
  • the oligomeric compound of embodiment 76, wherein the modified, unsubstituted 2’-deoxyfuranosyl sugar moiety is an unsubstituted a-D-2’-deoxyribosyl, a-L-2’-deoxyribosyl, -L-2’-deoxyribosyl, or b-D- 2’-deoxyxylosyl sugar moiety.
  • oligomeric compound of embodiment 78, wherein the bicyclic ribosyl sugar moiety is cEt, LNA, or ENA.
  • oligomeric compound of embodiment 62 wherein the one modified sugar moiety of the central region is a 2’-O-Methyl substituted ribosyl, unsubstituted a-D-2’-deoxyribosyl, unsubstituted a-L-2’- deoxyribosyl, or unsubstituted -L-2’-deoxyribosyl sugar moiety.
  • oligomeric compound of embodiment 63 wherein the one modified sugar moiety of the central region is a morpholino, 2’-0-Methyl substituted ribosyl, unsubstituted a-D-2’-deoxyribosyl, or unsubstituted b- L-2’-deoxyribosyl sugar moiety sugar moiety.
  • oligomeric compound of embodiment 64 wherein the one modified sugar moiety of the central region is a morpholino, unsubstituted a-D-2’-deoxyribosyl, or unsubstituted b-L-2’-deoxyribosyl sugar moiety sugar moiety.
  • oligomeric compound of embodiment 65 wherein the one modified sugar moiety of the central region is a 2’-F substituted ribosyl, 2’-MOE substituted ribosyl, 2’-0-Methyl substituted ribosyl, 5 -(.S ' )-Methyl substituted 2’-deoxyribosyl, 5’-allyl substituted 2’-deoxyribosyl, unsubstituted a-D-2’-deoxyribosyl, or cEt bicyclic sugar moiety.
  • oligomeric compound of embodiment 85 wherein the one modified sugar moiety of the central region is a 2’-MOE substituted ribosyl, 2’-0-Methyl substituted ribosyl, or 5’ -allyl substituted 2’-deoxyribosyl sugar moiety.
  • oligomeric compound of embodiment 88 wherein the one modified sugar moiety of the central region is a 2’-F substituted ribosyl, 2’-MOE substituted ribosyl, 2’-0-Methyl substituted ribosyl, 4’-Methyl substituted 2’-deoxyribosyl, 5’-(A)-Methyl substituted 2’-deoxyribosyl, 5 -(.V)-Ethyl substituted 2’- deoxyribosyl, 5’-(A)-Ethyl substituted 2’-deoxyribosyl, 5 -(.V)-Allyl substituted 2’-deoxyribosyl, 5 -(//)- Allyl substituted 2’-deoxyribosyl, 5’-stereorandom allyl substituted 2’-deoxyribosyl, unsubstituted b-E-2’- deoxyribo
  • oligomeric compound of embodiment 90 wherein the one modified sugar moiety of the central region is a morpholino, unsubstituted -L-2’-deoxyribosyl, or unsubstituted a-D-2’-deoxyribosyl sugar moiety.
  • oligomeric compound of embodiment 93 wherein the one modified sugar moiety of the central region is a 2’-F substituted ribosyl, 2’-MOE substituted ribosyl, 2’-0-Methyl substituted ribosyl, 5’-(S)-Methyl substituted 2’-deoxyribosyl, 5’-Allyl substituted 2’-deoxyribosyl, unsubstituted a-D-2’-deoxyribosyl, or cEt sugar moiety.
  • oligomeric compound of embodiment 93 wherein the one modified sugar moiety of the central region is a 2’-MOE substituted ribosyl, 2’-0-Methyl substituted ribosyl, 5’-(S)-Methyl substituted 2’- deoxyribosyl, 5’-Allyl substituted 2’-deoxyribosyl, or unsubstituted a-D-2’-deoxyribosyl sugar moiety.
  • oligomeric compound of embodiment 97 wherein the one modified sugar moiety of the central region is a 2’-F substituted ribosyl, 2’-MOE substituted ribosyl, 2’-0-Methyl substituted ribosyl, 4’-Methyl substituted 2’-deoxyribosyl, 5’-(A)-Methyl substituted 2’-deoxyribosyl, 5 -(.Y)-Ethyl substituted 2’- deoxyribosyl, 5’-(A)-Ethyl substituted 2’-deoxyribosyl, 5 -(.Y)-Allyl substituted 2’-deoxyribosyl, 5 -(//)- Allyl substituted 2’-deoxyribosyl, 5’-stereorandom allyl substituted 2’-deoxyribosyl, unsubstituted b-E-2’- deoxyribos
  • oligomeric compound of embodiment 100 wherein the one modified sugar moiety of the central region is a 2’-F substituted ribosyl, 2’-MOE substituted ribosyl, 2’-O-Methyl substituted ribosyl, 4’- Methyl substituted 2’-deoxyribosyl, 5’-(A)-Methyl substituted 2’-deoxyribosyl, 5’-( ⁇ S)-Methyl substituted 2’-deoxyribosyl, 5 -(.Y)-Ethyl substituted 2’-deoxyribosyl, 5’-(A)-Ethyl substituted 2’-deoxyribosyl, 5’- (,Y)-Allyl substituted 2’-deoxyribosyl, 5’-(A)-Allyl substituted 2’-deoxyribosyl, 5’-stereorandom allyl substituted 2’-deoxy
  • oligomeric compound of embodiment 100 wherein the one modified sugar moiety of the central region is a 2’-F substituted ribosyl, 2’-MOE substituted ribosyl, 2’-O-Methyl substituted ribosyl, 4’- Methyl substituted 2’-deoxyribosyl, 5’-(A)-Methyl substituted 2’-deoxyribosyl, 5 -(.V)- Ethyl substituted 2’-deoxyribosyl, 5 -(//) -Ethyl substituted 2’-deoxyribosyl, 5 -(.Y)-Allyl substituted 2’-deoxyribosyl, 5’- (A)-Allyl substituted 2’-deoxyribosyl, 5’-stereorandom allyl substituted 2’-deoxyribosyl, unsubstituted b- L-2’-deoxyrib
  • oligomeric compound of embodiment 103 wherein the one modified sugar moiety of the central region is a 2’-0-Methyl substituted ribosyl or unsubstituted b-L-2’-deoxyribosyl sugar moiety.
  • oligomeric compound of embodiment 103 wherein the one modified sugar moiety of the central region is an unsubstituted b-L-2’-deoxyribosyl sugar moiety.
  • oligomeric compound of embodiment 108 wherein the one modified sugar moiety of the central region is a 2’-0-Methyl substituted ribosyl, unsubstituted -L-2’-deoxyribosyl, or unsubstituted a-D-2’- deoxyribosyl sugar moiety.
  • oligomeric compound of embodiment 110 wherein the one modified sugar moiety of the central region is a 2’-0-Methyl substituted ribosyl, unsubstituted -L-2’-deoxyribosyl, or unsubstituted a-D-2’- deoxyribosyl sugar moiety.
  • oligomeric compound of embodiment 112 wherein the one modified sugar moiety of the central region is a 2’-0-Methyl substituted ribosyl or unsubstituted -L-2’-deoxyribosyl sugar moiety.
  • oligomeric compound of embodiment 123 wherein the 5’-alkyl substituted 2’-deoxyribosyl sugar moiety at position 2 of the central region is a 5’-allyl 2’-deoxyribosyl sugar moiety.
  • oligomeric compound of embodiment 127 wherein the modified, unsubstituted 2’- deoxyf iranosyl sugar moiety at position 2 of the central region is a a-D-2’-deoxyribosyl modified sugar moiety.
  • oligomeric compound of embodiment 130 wherein the 2’ -substituted ribosyl sugar moiety at position 3 of the central region is a 2’-F ribosyl sugar moiety.
  • the oligomeric compound of embodiment 134 wherein the 4’ -substituted 2’-deoxyribosyl sugar moiety at position 3 of the central region is a 4’-methyl 2’-deoxyribosyl sugar moiety.
  • oligomeric compound of embodiment 136 wherein the 5’-alkyl substituted 2’-deoxyribosyl sugar moiety at position 3 of the central region is a 5’-(i?)-ethyl 2’-deoxyribosyl sugar moiety.
  • the oligomeric compound of embodiment 146, wherein the modified, unsubstituted 2’- deoxyf iranosyl sugar moiety at position 3 of the central region is an -L-2’-deoxyribosyl modified sugar moiety.
  • oligomeric compound of embodiment 146 wherein the modified, unsubstituted 2’- deoxyf iranosyl sugar moiety at position 3 of the central region is an -D-2’-deoxyxylosyl modified sugar moiety.
  • the bicyclic ribosyl sugar moiety at position 3 of the central region is a cEt or LNA sugar moiety.
  • oligomeric compound of embodiment 160 wherein the 4’ -substituted 2’-deoxyribosyl sugar moiety at position 4 of the central region is a 4’-methyl 2’-deoxyribosyl sugar moiety.
  • oligomeric compound of embodiment 162 wherein the 5’-alkyl substituted 2’-deoxyribosyl sugar moiety at position 4 of the central region is a 5’-stereorandom methyl 2’-deoxyribosyl sugar moiety.
  • oligomeric compound of embodiment 162 wherein the 5’-alkyl substituted 2’-deoxyribosyl sugar moiety at position 4 of the central region is a 5 -(,S ' )-allyl 2’-deoxyribosyl sugar moiety.
  • oligomeric compound of embodiment 172 wherein the modified, unsubstituted 2’- deoxyf iranosyl sugar moiety at position 4 of the central region is an a-D-2’-deoxyribosyl modified sugar moiety.
  • oligomeric compound of embodiment 172, wherein the modified, unsubstituted 2’- deoxyf iranosyl sugar moiety at position 4 of the central region is an a-L-2’-deoxyribosyl modified sugar moiety.
  • the oligomeric compound of embodiment 172, wherein the modified, unsubstituted 2’- deoxyf iranosyl sugar moiety at position 4 of the central region is an -L-2’-deoxyribosyl modified sugar moiety.
  • oligomeric compound of embodiment 176 wherein the bicyclic ribosyl sugar moiety at position 4 of the central region is a cEt or LNA sugar moiety.
  • the oligomeric compound of embodiment 182 wherein the modified, unsubstituted T- deoxyf iranosyl sugar moiety at position 5 of the central region is a -L-2’-deoxyribosyl sugar moiety.
  • the oligomeric compound of embodiment 186 wherein the modified, unsubstituted T- deoxyf iranosyl sugar moiety at position 6 of the central region is a -L-2’-deoxyribosyl sugar moiety.
  • the oligomeric compound of embodiment 186, wherein the modified, unsubstituted T- deoxyf iranosyl sugar moiety at position 6 of the central region is an a-D-2’-deoxyribosyl sugar moiety.
  • the oligomeric compound of embodiment 190 wherein the modified, unsubstituted T- deoxyf iranosyl sugar moiety at position 7 of the central region is a -L-2’-deoxyribosyl sugar moiety.
  • the oligomeric compound of embodiment 190, wherein the modified, unsubstituted T- deoxyf iranosyl sugar moiety at position 7 of the central region is an a-D-2’-deoxyribosyl sugar moiety.
  • the oligomeric compound of embodiment 194, wherein the modified, unsubstituted T- deoxyf iranosyl sugar moiety at position 8 of the central region is a -L-2’-deoxyribosyl sugar moiety.
  • the oligomeric compound of embodiment 194, wherein the modified, unsubstituted 2’- deoxyfuranosyl sugar moiety at position 8 of the central region is an a-D-2’-deoxyribosyl sugar moiety.
  • oligomeric compound of any of embodiments 53-55 or 60-230, wherein the one modified intemucleoside linkage of the central region other than phosphorothioate is a phosphonate or
  • the oligomeric compound of embodiment 232, wherein the one modified intemucleoside linkage of the central region other than phosphorothioate is a methyl phosphonate intemucleoside linkage.
  • oligomeric compound of embodiment 231, wherein the one modified intemucleoside linkage of the central region other than phosphorothioate is a tetrahydropyran phosphotriester intemucleoside linkage.
  • intemucleoside linakge of the central region other than phosphorothioate is between the nucleosides at positions 1 and 2 of the central region.
  • intemucleoside linakge of the central region other than phosphorothioate is between the nucleosides at positions 2 and 3 of the central region.
  • intemucleoside linakge of the central region other than phosphorothioate is between the nucleosides at positions 3 and 4 of the central region.
  • intemucleoside linakge of the central region other than phosphorothioate is between the nucleosides at positions 4 and 5 of the central region.
  • intemucleoside linkage of the central region other than phosphorothioate is directly linked to a nucleoside comprising a modified sugar moiety.
  • oligomeric compound of embodiment 248, wherein at least one of the modified intemucleoside linkages of the central region other than phosphorothioate is an alkyl phosphonate or alkoxy phosphonate intemucleoside linkage.
  • oligomeric compound of embodiment 248, wherein at least one of the modified intemucleoside linkages of the central region other than phosphorothioate is a methoxypropyl intemucleoside linkage.
  • oligomeric compound of embodiment 248, wherein at least one of the modified intemucleoside linkages of the central region other than phosphorothioate is a phosphonoacetate intemucleoside linkage.
  • oligomeric compound of embodiment 248, wherein at least one of the modified intemucleoside linkages of the central region other than phosphorothioate is a thioacetamide intemucleoside linkage.
  • intemucleoside linkages other than phosphorothiaote of the central region are adjacent to each other.
  • the oligomeric compound of any of clamis 248-260, wherein the two modified intemucleoside linkages other than phosphorothioate of the central region are the same as one another.
  • the oligomeric compound of any of embodiments 248-261, wherein one of the modified intemucleoside linakges of the central region other than phosphorothioate is between the nucleosides at positions 1 and 2 of the central region.
  • intemucleoside linakges of the central region other than phosphorothioate is between the nucleosides at positions 2 and 3 of the central region.
  • intemucleoside linakges of the central region other than phosphorothioate is between the nucleosides at positions 3 and 4 of the central region.
  • intemucleoside linakges of the central region other than phosphorothioate is between the nucleosides at positions 4 and 5 of the central region.
  • intemucleoside linakges of the central region other than phosphorothioate is directly linked to a nucleoside comprising a modified sugar moiety.
  • oligomeric compound of any of embodiments 60-266, wherein the one modified nucleobase other than 5-methylcytosine of the central region is 2-thiothymine, 6-methyladenine, inosine, or pseudouracil.
  • oligomeric compound of embodiment 267, wherein the one modified nucleobase other than 5- methylcytosine is at position 1, 2, 3, or 4 of the central region.
  • oligomeric compound of embodiment 267, wherein the one modified nucleobase other than 5- methylcytosine is at position 2, 3, or 4 of the central region.
  • oligomeric compound of any of embodiments 267 or 270, wherein the one modified nucleobase other than 5-methylcytosine is 2-thiothymine.
  • oligomeric compound of any of embodiments 267 or 271, wherein the one modified nucleobase other than 5-methylcytosine is 6-methyladenine.
  • the oligomeric compound of any of embodiments 267 or 271, wherein the one modified nucleobase other than 5-methylcytosine is inosine.
  • oligomeric compound of any of embodiments 267-273, wherein the one modified nucleobase other than 5-methylcytosine is pseudouracil.
  • oligomeric compound of embodiment 277, wherein the nucleoside comprising the pseudouracil nucleobase comprises an unmodified ribosyl sugar moiety.
  • intemucleoside linkage of the central region is independently selected from among a phosphodiester or a phosphorothioate intemucleoside linkage.
  • each intemucleoside of the central region is a phosphorothioate intemucleoside linkage.
  • intemucleoside linkage of the oligomeric compound is strereorandom.
  • oligomeric compound of any of embodiments 1-281, wherein at least one phosphorothioate intemucleoside linkage of the oligomeric compound is in the Sp configuration.
  • the oligomeric compound of embodiment 292 or 293, wherein the target mRNA or target pre-mRNA is not a mouse, rat, monkey, or human SRB-l RNA.
  • the oligomeric compound of any of embodiments 292-294, wherein the target mRNA or target pre- mRNA is not a mouse, rat, monkey, or human MYD88 RNA.
  • RNA is a human RNA.
  • oligomeric compound of any of embodiments 285-297, wherein the target RNA is expressed in the liver is expressed in the liver.
  • oligomeric compound of any of embodiments 285-297, wherein the target RNA is not expressed in the liver is not expressed in the liver.
  • oligomeric compound of any of embodiments 285-299, wherein modulation of the expression of the target RNA in the liver is associated with treating a disorder or condition.
  • oligomeric compound of embodiment 302, wherein the disorder or condition is a liver disorder or condition.
  • oligomeric compound of any of embodiments 285-298, 300, 301, or 304, wherein the target RNA is a central nervous system target.
  • oligomeric compound of embodiment 308, wherein the target RNA is a MeCP2 RNA.
  • oligomeric compound of embodiment 308, wherein the target RNA is a DUX4 RNA.
  • oligomeric compound of embodiment 308, wherein the target RNA is a HDAC2 RNA.
  • oligomeric compound of embodiment 308, wherein the target RNA is a Ataxin 1 RNA.
  • oligomeric compound of embodiment 308, wherein the target RNA is a Ataxin 2 RNA.
  • oligomeric compound of embodiment 308, wherein the target RNA is a Ataxin 3 RNA.
  • oligomeric compound of embodiment 308, wherein the target RNA is a Ataxin 6 RNA.
  • oligomeric compound of embodiment 308, wherein the target RNA is a C90RF72 RNA.
  • oligomeric compound of embodiment 308, wherein the target RNA is an UBE3A RNA.
  • oligomeric compound of embodiment 308, wherein the target RNA is a Prion RNA.
  • oligomeric compound of embodiment 308, wherein the target RNA is a PMP22 RNA.
  • oligomeric compound of embodiment 308, wherein the target RNA is a Tau RNA.
  • oligomeric compound of embodiment 308, wherein the target RNA is a LRRK2 RNA.
  • oligomeric compound of embodiment 308, wherein the target RNA is an APP RNA.
  • oligomeric compound of embodiment 308, wherein the target RNA is a GYS 1 RNA.
  • oligomeric compound of embodiment 308, wherein the target RNA is a IRF8 RNA.
  • oligomeric compound of embodiment 308, wherein the target RNA is a Progranulin RNA.
  • oligomeric compound of embodiment 308, wherein the target RNA is a GFAP RNA.
  • oligomeric compound of embodiment 333 or 334 wherein the disorder or condition alters the function of sensory or motor neurons.
  • 336 The oligomeric compound of any of embodiments 333-335, wherein the disorder or condition alters the function of sensory neurons.
  • oligomeric compound of embodiment 338 wherein the disorder or condition alters the function of oligodendrocytes.
  • oligomeric compound of any of embodiments 333-342 wherein the disorder or condition is Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Parkinson’s Disease, a Spinocerebellar ataxia, Angelman Syndrome, Alexander’s Disease, Lafora Disease, Charcot-Marie Tooth Disease, Prion Disease, a dementia, neurodegeneration, MeCP2 Duplication Syndrome, encephalopathy, neuroinflammation, or multiple sclerosis.
  • oligomeric compound of embodiment 343, wherein the disorder or condition is Amyotrophic Lateral Sclerosis.
  • oligomeric compound of embodiment 343, wherein the disorder or condition is a Spinocerebellar ataxia.
  • oligomeric compound of embodiment 343, wherein the disorder or condition is Lafora Disease.
  • the oligomeric compound of embodiment 343, wherein the disorder or condition is Prion Disease. 353. The oligomeric compound of embodiment 343, wherein the disorder or condition is a dementia.
  • oligomeric compound of any of embodiments 1-358 wherein the parent oligomeric compound of the oligomeric compound of any of embodiments 1-358 is cytotoxic in vitro.
  • oligomeric compound of any of embodiments 1-360 wherein administration to a mouse of the parent oligomeric compound of the oligomeric compound of any of embodiments 1-360 is hepatotoxic to the mouse.
  • oligomeric compound of any of embodiments 361-363, wherein the mouse is a C57BL/6 mouse.
  • oligomeric compound of any of embodiments 361-363, wherein the mouse is a BALB/c mouse.
  • oligomeric compound of any of embodiments 361-366 wherein the plasma AST level in the mouse is higher than 1000 units per liter following the administration of the parent oligomeric compound.
  • 371. The oligomeric compound of any of embodiments 361-370, wherein the hepatotoxicity is measured 24-48 hours following the administration of the parent oligomeric compound.
  • oligomeric compound of any of embodiments 1-383 wherein administration of 50 mg/kg of the oligomeric compound of any of embodiments 1-383 to a mouse is not hepatotoxic to the mouse.
  • oligomeric compound of embodiment 384 wherein plasma ALT level in the mouse is lower than 100 units per liter following the administration of the oligomeric compound of embodiment 384.
  • oligomeric compound of embodiment 384 or 385 wherein plasma ALT level in the mouse is at least 10-fold lower than plasma ALT level in a mouse administered the parent oligomeric compound of the oligomeric compound of embodiment 384 or 385, wherein the administrations and plasma ALT measurements of both the oligomeric compound of embodiment 384 or 385 and the parent oligomeric compound are completed in the same way.
  • oligomeric compound of embodiment 389 wherein the therapeutic index in a mouse of the oligomeric compound of embodiment 365 is at least two-fold greater than the therapeutic index of the parent oligomeric compound.
  • oligomeric compound of any of embodiments 1-390 wherein an otherwise identical oligomeric compound lacking the at least one modified intemucleoside linkage other than phosphorothioate and/or at least one modified nucleoside comprising a modified nucleobase other than 5-methylcytosine and/or a modified sugar moiety in the central region is hepatotoxic following administration to a mouse; and wherein the otherwise identical oligomeric compound has a central region consisting of phosphorothioate intemucleoside linkages, unmodified 2’- -D-deoxyribosyl sugar moieties, and nucleobases selected from thymine, uracil, adenine, guanine, cytosine, and 5-methylcytosine.
  • oligomeric compound of embodiment 391, wherein the at least one modified intemucleoside linkage other than phosphorothioate and/or at least one modified nucleoside comprising a modified nucleobase other than 5-methylcytosine and/or a modified sugar moiety in the central region is a 2’- O-methyl modified sugar moiety.
  • oligomeric compound is a parent oligomeric compound of the oligomeric compound of any of embodiments 391-395. 397. The oligomeric compound of any of embodiments 285-396, wherein the oligomeric compound inhibits the target RNA with an IC50 lower than 100 nM in a standard in vitro activity assay.
  • oligomeric compound of any of embodiments 285-397 wherein the parent oligomeric compound of the oligomeric compound of any of embodiments 285-397 inhibits the target RNA with an IC50 lower than 100 nM in a standard in vitro activity assay.
  • oligomeric compound of any of embodiments 285-398 wherein the difference between the IC50 of the parent oligomeric compound measured in a standard in vitro activity assay and the IC50 of the oligomeric compound of any of embodiments 285-398 measured in a standard in vitro activity assay is less than 4-fold.
  • oligomeric compound of any of embodiments 285-398 wherein the difference between the IC50 of the parent oligomeric compound measured in a standard in vitro activity assay and the IC50 of the oligomeric compound of any of embodiments 285-398 measured in a standard in vitro activity assay is less than 3-fold.
  • oligomeric compound of any of embodiments 285-398 wherein the difference between the IC50 of the parent oligomeric compound measured in a standard in vitro activity assay and the IC50 of the oligomeric compound of any of embodiments 285-398 measured in a standard in vitro activity assay is less than 2-fold.
  • each sugar moiety of the central region of the parent oligomeric compound is an unmodified 2’- -D-deoxyribosyl sugar moiety, and wherein each intemucleoside linkage of the central region of the parent oligomeric compound is a phosphorothioate intemucleoside linkage.
  • a composition comprising the oligomeric compound of any of embodiments 1-407 and a second oligomeric compound, wherein the second oligomeric compound is complementary to the oligomeric compound of any of embodiments 1-407. 409.
  • the composition of embodiment 408, wherein the second oligomeric compound comprises at least 14 contiguous linked nucleosides that are at least 90% complementary to the oligomeric compound of any of embodiments 1-407.
  • composition of embodiment 408, wherein the second oligomeric compound comprises at least 14 contiguous linked nucleosides that are 100% complementary to the oligomeric compound of any of embodiments 1-407.
  • a pharmaceutical composition comprising the oligomeric compound of any of embodiments 1-407 or the composition of any of embodiments 408-410, comprising a pharmaceutically acceptable carrier or diluent.
  • a method comprising administering the oligomeric compound or composition of any of
  • embodiments 1-411 to a human subject.
  • a method of treating a disease or disorder comprising administering the oligomeric compound or composition of any of embodiments 1-411 to a human subject.
  • a method of modulating the amount or activity of a target RNA in a human subject comprising
  • oligomeric compound or composition of any of embodiments 1-411 to the human subject; and thereby modulating the amount or activity of the target RNA in the human subject.
  • a method of treating a disease or disorder in a human subject comprising administering the
  • oligomeric compound or composition of any of embodiments 1-411 to the human subject having the disease or disorder; and thereby treating the disease or disorder in the human subject.
  • oligomeric compound modulates the amount or activity of a liver target RNA.
  • the disease or disorder is a cancer, a neurodegenerative disease, a cardiovascular disease, an immunological disease, a hereditary disease, a repeat expansion disease, a muscle -wasting disease, or a metabolic disease.
  • each sugar moiety of the central region of the parent oligomeric compound is an unmodified 2’- -D-deoxyribosyl sugar moiety, and wherein each intemucleoside linkage of the central region of the parent oligomeric compound is a
  • a method of designing an oligomeric compound comprising starting with a parent oligomeric
  • a method of designing an oligomeric compound comprising identifying a parent oligomeric
  • the second oligomeric compound is an oligomeric compound of any one of embodiments 1-407.
  • a method of improving hepatotoxicity of an oligomeric compound comprising the steps of (i)
  • identifying a parent oligomeric compound that has plasma ALT levels above 300 units per liter in a mouse and (ii) providing an oligomeric compound according to any one of embodiments 1-407.
  • embodiments 1-407 has reduced hepatotoxicity relative to the parent oligomeric compound.
  • a method comprising administering an oligomeric compound of any of embodiments 1-407 to a mouse and separately administering the parent oligomeric compound of the oligomeric compound of any of embodiments 1-407 to a second mouse, wherein the therapeutic index of the oligomeric compound of any of embodiments 1-407 is improved relative to the therapeutic index of the parent oligomeric compound.
  • mouse the cell, and/or the human subject.
  • a method comprising administering an oligomeric compound to a subject and measuring the level of p2l RNA in the subject.
  • a method comprising administering an oligomeric compound of any of embodiments 1-407 to a subject and measuring the level of p2l RNA in the subject.
  • a method comprising contacting a cell with an oligomeric compound and detecting the cellular localization of p54nrb protein in the cell.
  • a method of screening for a tolerable oligomeric compound comprising any of the methods of
  • An oligomeric compound comprising a modified oligonucleotide consisting of 12-23 linked
  • modified oligonucleotide comprises a 5’-region, a central region, and a 3’- region wherein:
  • the 5’-region consists of 1-5 linked modified nucleosides
  • the 3’-region consists of 1-5 linked modified nucleosides; and the central region consists of 7-11 linked nucleosides and has the formula:
  • N x , N y , and N z are safety enhancing nucleoside
  • N x , N y , and N z are independently selected from an unmodified 2’- -D-deoxyribosyl, a DNA isomer, and a DNA mimic;
  • N di and each N d is independently selected from an unmodified 2’- -D-deoxyribosyl, a DNA isomer, and a DNA mimic; and wherein
  • oligomeric compound of embodiment 1, wherein the safety enhancing nucleoside is N x or N y .
  • a sugar moiety selected from among a sugar surrogate, a bicyclic furanosyl sugar moiety, a non- bicyclic 2’-modified furanosyl sugar moiety, a non-bicyclic 4’-modified furanosyl sugar moiety, or a non-bicyclic 5’-modified furanosyl sugar moiety.
  • a sugar moiety selected from among a morpholino, a 2’-0-methyl-2’- -D-deoxyribosy sugar moiety, a cEt bicyclic sugar moiety, a LNA sugar moiety, an ENA sugar moiety, a 5’
  • oligomeric compound of embodiment 461, wherein the sugar surrogate is selected from among a morpholino, a modified morpholino, and F-HNA.
  • each DNA isomer has a sugar moiety independently selected from among 2’- -D-deoxyxylosyl, 2’-a-L-deoxyribosyl, 2 -b- ⁇ - deoxyribosyl, 2’-a-D-deoxyxylosyl, 1, 2’-a-L-deoxyxylosyl, and 2’- -L-deoxyxylosyl.
  • oligomeric compound of any of embodiments 452-467, wherein each DNA mimic has a sugar moiety is independently selected from among 5’-methyl-2’- -D-deoxyribosyl and 5’-ethyl-2’- -D- deoxyribosyl.
  • each nucleoside of the central region other than the safety-enhancing nucleoside has a 2’- -D-deoxyribosyl sugar moiety.
  • linkages are phosphorothioate linkages.
  • intemucleoside linkage is a phosphonate intemucleoside linkage.
  • intemucleoside linkage is a methoxypropyl intemucleoside linkage.
  • oligomeric compound of any of embodiments 452-475 wherein at least one intemucleoside linkage of the central region selected from among: the intemucleoside Ndl to Nx, Nx to Ny, Ny to Nz, or Nz to the adjacent Nd is a neutral intemucleoside linkage.
  • oligomeric compound of embodiment 475, wherein the modified oligonucleotide comprises one neutral linkage and the other intemucleoside linkages are each independently selected from phosphodiester and phosphorothioate.
  • each nucleoside of the 5’- region comprises a bicyclic furanosyl sugar moiety.
  • each non-bicyclic sugar moiety of the 5’-region has a 2’-substituent selected from among 2’-MOE, 2’-OMe, and 2’-NMA.
  • oligomeric compound of any of embodiments 477-480, wherein the 5’-region comprises a 2’- MOE modified nucleoside and a cEt modified nucleoside.
  • each nucleoside of the 3’-region comprises a bicyclic furanosyl sugar moiety.
  • each bicyclic sugar moiety of the 3’-region is selected from among cEt, LNA, and ENA.
  • each non-bicyclic sugar moiety of the 3’-region has a 2’-substituent selected from among 2’-MOE, 2’-OMe, and 2’-NMA.
  • each nucleoside of the 5’-region comprises a bicyclic furanosyl sugar moiety and each nucleoside of the 3’-region comprises a non- bicyclic sugar moiety.
  • each nucleoside of the 5’-region comprises an LNA sugar moiety and each nucleoside of the 3’-region comprises a 2’MOE sugar moiety.
  • each nucleoside of the 5’-region comprises cEt sugar moiety and each nucleoside of the 3’-region comprises a 2’MOE sugar moiety.
  • oligomeric compound of embodiment 501 wherein the target RNA encodes a protein that is expressed in the liver.
  • oligomeric compound of embodiment 502 wherein the target RNA encodes a protein that is expressed in the CNS.
  • oligomeric compound of any of embodiments 452-503, wherein the oligomeric compound is not toxic is not toxic.
  • oligomeric compound of embodiment 505 wherein administering a dose of the oligomeric compound to an animal results in a circulating ALT level that is at least 3 -fold lower than the ALT level that results from administering the same dose of the comparator compound to an animal for at least one matched dose.
  • the oligomeric compound of embodiment 508 wherein the oligomeric compound has RNA-reducing activity comparable to a comparator compound, wherein the comparator compound is identical to the oligomeric compound except that each nucleoside of the central region of the comparator compound is a nucleoside comprising 2’- -D-deoxyribosyl sugar moiety.
  • the oligomeric compound of embodiment 509 having RNA-reducing activity that is no more than 2- fold worse than the RNA-reducing activity of the comparator compound.
  • An oligomeric compound comprising a modified oligonucleotide consisting of 12-23 linked
  • modified oligonucleotide comprises a 5’-region, a central region, and a 3’- region wherein:
  • the 5’-region consists of 1-5 linked nucleosides; wherein at least one 5’-region nucleoside is modified;
  • the 3’-region consists of 1-5 linked nucleosides; wherein at least one 3’-region nucleoside is modified;
  • the central region consists of 7-11 linked nucleosides, and has the formula:
  • N di , N d2 , N d3 , N d4 , and each N d are independently selected from among
  • nucleoside comprising an unmodified 2’- -D-deoxyribosyl sugar moiety, a DNA isomer sugar moiety, or a DNA mimic sugar moiety;
  • each Ll, L2, L3, and L4 is an intemucleoside linkage
  • Ll, L2, L3, and L4 is a neutral intemucleoside linkage.
  • a method comprising administering the oligomeric compound or composition of any of
  • embodiments 452-517 to a human subject.
  • a method of treating a disease or disorder comprising administering the oligomeric compound or composition of any of embodiments 452-517 to a human subject.
  • a method of modulating the amount or activity of a target RNA in a human subject comprising administering the oligomeric compound or composition of any of embodiments 452-517 to the human subject; and thereby modulating the amount or activity of the target RNA in the human subject.
  • a method of treating a disease or disorder in a human subj ect comprising administering the oligomeric compound or composition of any of embodiments 452-517 to the human subject having the disease or disorder; and thereby treating the disease or disorder in the human subject.
  • oligomeric compound modulates the amount or activity of a liver target RNA.
  • neurodegenerative disease a cardiovascular disease, an immunological disease, a hereditary disease, a repeat expansion disease, a muscle -wasting disease, or a metabolic disease.
  • each sugar moiety of the central region of the parent oligomeric compound is an unmodified 2’- -D-deoxyribosyl sugar moiety, and wherein each intemucleoside linkage of the central region of the parent oligomeric compound is a
  • a method of designing an oligomeric compound comprising starting with a parent oligomeric
  • a method of designing an oligomeric compound comprising identifying a parent oligomeric
  • the second oligomeric compound is an oligomeric compound of any one of embodiments 452-517.
  • a method of improving hepatotoxicity of an oligomeric compound comprising the steps of (i)
  • identifying a parent oligomeric compound that has plasma ALT levels above 300 units per liter in a mouse and (ii) providing an oligomeric compound according to any one of embodiments 452-517.
  • embodiments 452-517 has reduced hepatotoxicity relative to the parent oligomeric compound.
  • a method comprising administering an oligomeric compound of any of embodiments 452-517 to a mouse and separately administering the parent oligomeric compound of the oligomeric compound of any of embodiments 452-517 to a second mouse, wherein the therapeutic index of the oligomeric compound of any of embodiments 452-517 is improved relative to the therapeutic index of the parent oligomeric compound.
  • mouse the cell, and/or the human subject.
  • a method comprising administering an oligomeric compound of any of embodiments 452-517 to a subject and measuring the level of p2l RNA in the subject.
  • oligomeric compound comprising a modified oligonucleotide consisting of 12-21 linked nucleosides, wherein the modified oligonucleotide has the formula A-B-C, wherein A is a 5’-region, B is a central region, and C is a 3’-region; wherein:
  • the 5’-region consists of 1-5 linked nucleosides, wherein at least one nucleoside of the 5’-region is a modified nucleoside comprising a modified sugar;
  • the 3’-region consists of 1-5 linked nucleosides wherein at least one nucleoside of the 3’-region is a modified nucleoside comprising a modified sugar;
  • the central region consists of 7-11 linked nucleosides, wherein
  • N x , N y , and N z are safety-enhancing nucleoside
  • N x , N y , and N z are independently selected from a DNA nucleoside, a DNA isomer, a modified DNA isomer, and a DNA mimic;
  • N da and N* are each independently selected from a DNA nucleoside, a DNA isomer, a modified DNA isomer, and a DNA mimic.
  • each nucleoside of the 5’-region is a modified nucleoside.
  • each nucleoside of the 5’-region is a modified nucleoside comprising a modified sugar.
  • each nucleoside of the 5’-region comprises a 2’-modified ribosyl sugar moiety.
  • each nucleoside of the 5’-region comprises a bicyclic furanosyl sugar moiety.
  • oligomeric compound of embodiment 566 wherein the non-bicyclic sugar moiety of the at least one nucleoside of the 5’-region is a 2’-substituted ribosyl sugar moiety.
  • each nucleoside of the 5’-region comprises a non-bicyclic sugar moiety.
  • each nucleoside of the 5’-region comprises a 2’ -substituted furanosyl sugar moiety.
  • each nucleoside of the 5’-region comprises a 2’-modified furanosyl sugar moiety independently selected from a bicyclic sugar moiety and a non-bicyclic 2’ -substituted ribosyl sugar moiety.
  • each nucleoside of the 5’-region comprises a bicyclic sugar moiety.
  • each nucleoside of the 5’-region comprises a non-bicyclic 2’-substituted ribosyl sugar moiety.
  • each bicyclic sugar moiety of the 5’-region is selected from among cEt, LNA, and ENA.
  • each bicyclic sugar moiety of the 5’-region is a cEt sugar moiety.
  • each bicyclic sugar moiety of the 5’-region is an LNA sugar moiety.
  • each non-bicyclic sugar moiety of the 5’-region has a 2’-substituent selected from among 2’-MOE, 2’-OMe, and 2’-NMA.
  • each nucleobase of the 5’-region is independently selected from among thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.
  • each intemucleoside linkage of the 5’-region is selected from among phosphodiester and phosphorothioate intemucleoside linkages.
  • each nucleoside of the 3’-region is a modified nucleoside.
  • each nucleoside of the 3’-region is a modified nucleoside comprising a modified sugar moiety.
  • each nucleoside of the 3’-region comprises a 2’-modified ribosyl sugar moiety.
  • 596 The oligomeric compound of any of embodiments 551-595, wherein at least one nucleoside of the 3’- region comprises a bicyclic furanosyl sugar moiety.
  • each nucleoside of the 3’-region comprises a bicyclic furanosyl sugar moiety.
  • oligomeric compound of embodiment 598 wherein the non-bicyclic sugar moiety of the at least one nucleoside of the 3’-region is a 2’-substituted ribosyl sugar moiety.
  • each nucleoside of the 3’-region comprises a non-bicyclic sugar moiety.
  • each nucleoside of the 3’-region comprises a 2’ -substituted furanosyl sugar moiety.
  • each nucleoside of the 3’-region comprises a 2’-modified furanosyl sugar moiety independently selected from a bicyclic sugar moiety and a non-bicyclic 2’ -substituted ribosyl sugar moiety.
  • each nucleoside of the 3’-region comprises a bicyclic sugar moiety.
  • each nucleoside of the 3’-region comprises a non-bicyclic 2’-substituted ribosyl sugar moiety.
  • each bicyclic sugar moiety of the 3’-region is selected from among cEt, LNA, and ENA.
  • each bicyclic sugar moiety of the 3’-region is a cEt sugar moiety.
  • each bicyclic sugar moiety of the 3’-region is an LNA sugar moiety.
  • the oligomeric compound of any of embodiments 551-611, wherein none of the nucleosides of the 3’-region comprise a cEt sugar moiety. 613.
  • the oligomeric compound of any of embodiments 551-612, wherein none of the nucleosides of the 3’-region comprise a LNA sugar moiety.
  • each nucleobase of the 3’-region is independently selected from among thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.
  • each intemucleoside linkage of the 3’-region is selected from among phosphodiester and phosphorothioate intemucleoside linkages.
  • oligomeric compound of any of embodiments 551-617, wherein the 5’-region and the 3’-region together include at least one non-bicyclic 2’ -substituted modified nucleoside and at least one bicyclic nucleoside.
  • each N dC is independently selected from an unmodified DNA nucleoside, a DNA isomer, a 2’- modified DNA isomer, and a DNA mimic; and q is 2-6.
  • the safety enhancing nucleoside is a DNA isomer comprising a sugar moiety selected from among 2’- -D-deoxyxylosyl, 2’-a-L- deoxyribosyl, 2’- -L-deoxyribosyl, 2’-a-D-deoxyxylosyl, and 2’- -L-deoxyxylosyl.
  • the safety enhancing nucleoside is a modified DNA isomer comprising a 2’ -modified sugar moiety, wherein the sugar moiety has the conformation 2’- -D-deoxyxylosyl, 2’-a-L-deoxyribosyl, 2’- -L-
  • the safety enhancing nucleoside is a modified DNA isomer comprising a 2’ -modified sugar moiety, wherein the sugar moiety has the conformation 2’- -D-deoxyxylosyl, 2’-a-L-deoxyribosyl, 2’- -L-deoxyribosyl
  • oligomeric compound of any of embodiments 551-634 wherein the safety enhancing nucleoside is a modified DNA isomer comprising a sugar moiety selected from among 2’- -D-deoxyxylosyl, T- a-L-deoxyribosyl, and 2’- -L-deoxyribosyl and the T position is further substituted with a hydroxyl, fluoro, or OMe substituent.
  • oligomeric compound of embodiment 645, wherein the 2’-substitued furanosyl sugar moiety of the safety enhancing nucleoside has a 2’ substituent selected from: fluoro, OMe, MOE, NMA.
  • the safety enhancing nucleoside comprises a 3’-modified furanosyl sugar moiety having a 3’ substituent selected from: halo, allyl, amino, azido, SH, CN, CF 3 , OCF 3 , C1-C10 alkyl, C1-C10 substituted alkyl, S-alkyl, N(R m )-alkyl, N(R m )-alkenyl, N(R m )-alkynyl, O-alkylenyl-O-alkyl, alkynyl, alkaryl, or aralkyl.
  • a 3’ substituent selected from: halo, allyl, amino, azido, SH, CN, CF 3 , OCF 3 , C1-C10 alkyl, C1-C10 substituted alkyl, S-alkyl, N(R m )-alkyl, N(R m )-alkenyl, N(R
  • the safety enhancing nucleoside comprises a 4’-modified furanosyl sugar moiety having a 4’ substituent selected from: halo, allyl, amino, azido, SH, CN, OCN, CF3, OCF3, O-Ci-Cio alkoxy, O-Ci-Cio substituted alkoxy, C1-C10 alkyl, C1-C10 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, 0(CH 2 ) 2
  • oligomeric compound of any of embodiments 551-634, wherein the safety enhancing nucleoside has the structure shown below, wherein R represents an optional 2’ substituent group and Bx is a heterocyclic base moiety:
  • oligomeric compound of any of embodiments 551-666, wherein the safety enhancing nucleoside comprises a hypoxanthine nucleobase comprises a hypoxanthine nucleobase.
  • a DNA nucleoside selected from among a DNA nucleoside, a DNA isomer, a modified DNA isomer, and a DNA mimic.
  • each DNA isomer comprises a sugar moiety selected from among 2’- -D-deoxyxylosyl, 2’-a-L-deoxyribosyl, 2’- -L-deoxyribosyl, 2’-a-D- deoxyxylosyl, 2’-a-D-deoxyribosyl, 2’-a-L-deoxyxylosyl, and 2’- -L-deoxyxylosyl. 672.
  • each DNA isomer comprises a sugar moiety selected from among 2’ ⁇ -D-deoxyxylosyl, 2’-a-L-deoxyribosyl, and 2’ ⁇ -L-deoxyribosyl.
  • each modified DNA isomer comprises a 2’- modified sugar moiety, wherein the sugar moiety has the conformation 2’ ⁇ -D-deoxyxylosyl, 2’-a-L- deoxyribosyl, 2’ ⁇ -L-deoxyribosyl, 2’-a-D-deoxyxylosyl, 1, 2’-a-L-deoxyxylosyl, and 2 -b- ⁇ - deoxyxylosyl and the 2’ position is further substituted with a hydroxyl, a fluoro, or O-C1-C10 alkoxy substituent.
  • each modified DNA isomer comprises a 2’- modified sugar moiety, wherein the sugar moiety has the conformation 2’ ⁇ -D-deoxyxylosyl, 2’-a- L-deoxyribosyl, 2’ ⁇ -L-deoxyribosyl, 2’-a-D-deoxyxylosyl, 1, 2’-a-L-deoxyxylosyl, and 2 -bA- deoxyxylosyl and the 2’ position is further substituted with a hydroxyl, a fluoro, or OMe substituent.
  • each modified DNA isomer comprises a 2’- modified sugar moiety, wherein the sugar moiety has the conformation 2’ ⁇ -D-deoxyxylosyl, 2’-a- L-deoxyribosyl, 2’ ⁇ -L-deoxyribosyl, 2’-a-D-deoxyxylosyl, 1, 2’-a-L-deoxyxylosyl, and 2 -bA- deoxyxylosyl and the 2’ position is further substituted with a fluoro or OMe substituent.
  • each modified DNA isomer comprises a 2’- modified sugar moiety, wherein the sugar moiety is selected from among 2’ ⁇ -D-deoxyxylosyl, 2’-a- L-deoxyribosyl, and 2’ ⁇ -L-deoxyribosyl and the 2’ position is further substituted with a hydroxyl, fluoro, or OMe substituent.
  • each DNA mimic comprises a structure represented by one of the formulas below:
  • X is O or S and Bx represents a heteorcylic base moiety.
  • each DNA mimic comprises a structure represented by one of the formulas below:
  • X is O or S
  • Bx represents a heterocyclic base moiety
  • Rl is selected from among H, OH, halo, allyl, amino, azido, SH, CN, OCN, CF 3 , OCF 3 , O-Ci-Cio alkoxy, O- C 1 -C 10 substituted alkoxy, C 1 -C 10 alkyl, C 1 -C 10 substituted alkyl, S-alkyl, N(Rm)-alkyl, O-alkenyl, S-alkenyl, N(Rm)- alkenyl, O-alkynyl, S-alkynyl, N(R m )-alkynyl, O-alkylenyl-O-alkyl, alkynyl, alkaryl, aralkyl, O- alkaryl, O-aralkyl, 0(CH 2 ) 2 SCH 3 , 0(CH 2 ) 2 0N(R
  • each DNA mimic comprises a stmcture represented by the formula below: ; wherein X is O, Bx represents a heterocyclic base moiety, and Rl is H.
  • oligomeric compound of embodiment 670, wherein DNA mimic has a sugar moiety selected from among: 5’-methyl-2’ ⁇ -D-deoxyribosyl, 5’-ethyl-2’ ⁇ -D-deoxyribosyl, and 5 -h11n1-2 -b- ⁇ - deoxyribosyl.
  • oligomeric compound of embodiment 670, wherein DNA mimic comprises a 2 - ⁇ 1i ⁇ 0G0-b- ⁇ - arabinofuranosyl sugar moiety
  • oligomeric compound of embodiment 670, wherein the DNA mimic does not comprise a 2’- fluoro ⁇ -D-arabinofuranosyl sugar moiety.
  • central region has at least one particular phorphorothioate intemucleoside linkage having a particular stereochemical configuration.
  • intemucleoside linkage of the central region has the (rip) configuration.
  • phosphorothioate intemucleoside linkage that does not have the (rip) or (rip) configuration is stereorandom.
  • the oligomeric compound of any of embodiments 551-704 comprising a conjugate group. 706.
  • oligomeric compound of embodiment 711 wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to the target RNA.
  • the oligomeric compound of embodiment 713, wherein the target mRNA or target pre-mRNA is not a mouse, rat, monkey, or human PTEN RNA.
  • the oligomeric compound of embodiment 713 or 714, wherein the target mRNA or target pre-mRNA is not a mouse, rat, monkey, or human SRB-l RNA.
  • oligomeric compound of any of embodiments 708-718, wherein the target RNA is expressed in the liver is expressed in the liver.
  • oligomeric compound of any of embodiments 708-718, wherein the target RNA is not expressed in the liver is not expressed in the liver.
  • oligomeric compound of embodiment 723, wherein the disorder or condition is a liver disorder or condition.
  • oligomeric compound of any of embodiments 708-724, wherein the target RNA is expressed in the central nervous system is expressed in the central nervous system.
  • RNA is a MeCP2, DUX4, HDAC2, APP, Ataxin 1, Ataxin 2, Ataxin 3, Ataxin 6, Ataxin 7, C90RF72, UBE3A, Prion, PMP22, Tau, LRRK2, LING02, GYS1, KCNT1, IRF8, Progranulin, or GFAP RNA.
  • oligomeric compound of embodiment 729, wherein the target RNA is a MeCP2 RNA.
  • oligomeric compound of embodiment 729, wherein the target RNA is a Ataxin 2 RNA.
  • oligomeric compound of embodiment 729, wherein the target RNA is a Ataxin 6 RNA.
  • oligomeric compound of embodiment 708-727, wherein the target RNA is an alpha-synuclein RNA.
  • oligomeric compound of embodiment 729, wherein the target RNA is an UBE3 A RNA.
  • RNA. 747 The oligomeric compound of any of embodiments 708-727, wherein the target RNA is an APP RNA.
  • oligomeric compound of any of embodiments 708-727, wherein the target RNA is a GYS 1 RNA.
  • oligomeric compound of any of embodiments 708-727, wherein the target RNA is a IRF8 RNA.
  • oligomeric compound of any of embodiments 725-753, wherein modulation of the expression of the target RNA in the central nervous system is associated with treating a disorder or condition.
  • oligomeric compound of embodiment 754 wherein the disorder or condition is a neurological disorder or condition.
  • oligomeric compound of embodiment 764, wherein the disorder or condition is Amyotrophic Lateral Sclerosis.
  • oligomeric compound of any of embodiments 551-779, wherein the parent oligomeric compound of the oligomeric compound of any of embodiments 551-779 is cytotoxic in vitro.
  • oligomeric compound of any of embodiments 551-781 wherein administration to a mouse of the parent oligomeric compound of the oligomeric compound of any of embodiments 551-781 is hepatotoxic to the mouse. 783.
  • the oligomeric compound of embodiment 782, wherein the administration of the parent oligomeric compound to the mouse is systemic administration.
  • oligomeric compound of any of embodiments 782-784, wherein the mouse is a BALB/c mouse.
  • oligomeric compound of any of embodiments 551-804 wherein administration of 50 mg/kg of the oligomeric compound of any of embodiments 551-804 to a mouse is not hepatotoxic to the mouse.
  • oligomeric compound of embodiment 805 wherein plasma ALT level in the mouse is lower than 100 units per liter following the administration of the oligomeric compound of embodiment 805.
  • oligomeric compound of embodiment 807 wherein the plasma ALT level in the mouse is at least lOO-fold lower than the plasma ALT level in the mouse administered the parent oligomeric compound.
  • oligomeric compound of embodiment 807 wherein the plasma ALT level in the mouse is at least 500-fold lower than the plasma ALT level in the mouse administered the parent oligomeric compound.
  • oligomeric compound of any of embodiments 782-809 wherein the therapeutic index in a mouse of the oligomeric compound of any of embodiments 782-809 is increased relative to the therapeutic index of the parent oligomeric compound.
  • oligomeric compound of embodiment 810 wherein the therapeutic index in a mouse of the oligomeric compound of embodiment 365 is at least two-fold greater than the therapeutic index of the parent oligomeric compound.
  • oligomeric compound of any of embodiments 551-811 wherein an otherwise identical oligomeric compound lacking the at least one modified intemucleoside linkage other than phosphorothioate and/or at least one modified nucleoside comprising a modified nucleobase other than 5-methylcytosine and/or a modified sugar moiety in the central region is hepatotoxic following administration to a mouse; and wherein the otherwise identical oligomeric compound has a central region consisting of phosphorothioate intemucleoside linkages, unmodified 2’- -D-deoxyribosyl sugar moieties, and nucleobases selected from thymine, uracil, adenine, guanine, cytosine, and 5-methylcytosine.
  • oligomeric compound of embodiment 812 wherein the at least one modified intemucleoside linkage other than phosphorothioate and/or at least one modified nucleoside comprising a modified nucleobase other than 5-methylcytosine and/or a modified sugar moiety in the central region is a 2’- O-methyl modified sugar moiety.
  • oligomeric compound lacks a 2’-O-methyl modified sugar moiety, and wherein the otherwise identical oligomeric compound comprises an unmodified 2’- -D-deoxyribosyl sugar moiety in place of the 2’- O-methyl modified sugar moiety.
  • oligomeric compound is a parent oligomeric compound of the oligomeric compound of any of embodiments 812-816.
  • oligomeric compound of any of embodiments 708-818 wherein the parent oligomeric compound of the oligomeric compound of any of embodiments 708-818 inhibits the target RNA with an IC50 lower than 100 nM in a standard in vitro activity assay.
  • oligomeric compound of any of embodiments 708-819 wherein the difference between the IC50 of the parent oligomeric compound measured in a standard in vitro activity assay and the IC50 of the oligomeric compound of any of embodiments 708-819 measured in a standard in vitro activity assay is less than 4-fold.

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Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021021673A1 (en) 2019-07-26 2021-02-04 Ionis Pharmaceuticals, Inc. Compounds and methods for modulating gfap
WO2021084495A1 (en) 2019-11-01 2021-05-06 Novartis Ag The use of a splicing modulator for a treatment slowing progression of huntington's disease
US11149264B2 (en) 2018-02-12 2021-10-19 Ionis Pharmaceuticals, Inc. Modified compounds and uses thereof
WO2021202788A3 (en) * 2020-04-03 2021-11-11 Ionis Pharmaceuticals, Inc. Modified oligomeric compounds and uses thereof
US11359199B2 (en) 2019-03-20 2022-06-14 President And Fellows Of Harvard College Antisense oligonucleotide-based progranulin augmentation therapy in neurodegenerative diseases
US11447521B2 (en) 2020-11-18 2022-09-20 Ionis Pharmaceuticals, Inc. Compounds and methods for modulating angiotensinogen expression
WO2022208170A1 (en) 2021-03-29 2022-10-06 Novartis Ag The use of the splicing modulator brataplam for slowing progression of huntington's disease
WO2022266414A1 (en) * 2021-06-18 2022-12-22 Ionis Pharmaceuticals, Inc. Compounds and methods for reducing ifnar1 expression
US11629348B2 (en) 2019-08-15 2023-04-18 Ionis Pharmaceuticals, Inc. Linkage modified oligomeric compounds and uses thereof
WO2023075766A1 (en) * 2021-10-27 2023-05-04 Wave Life Sciences Ltd. Oligonucleotide compositions and methods of use thereof
JP2023527330A (ja) * 2020-05-28 2023-06-28 コロ バイオ， インコーポレイテッド Ｓｅｒｐｉｎａ１のａｄａｒ媒介編集のための方法及び組成物
JP2023530072A (ja) * 2020-06-19 2023-07-13 アイオーニス ファーマシューティカルズ， インコーポレーテッド Ｐｍｐ２２を調節するための化合物及び方法
US20240336915A1 (en) * 2021-01-22 2024-10-10 Ionis Pharmaceuticals, Inc. Compounds and methods for reducing dux4 expression
WO2024220746A2 (en) 2023-04-21 2024-10-24 Flagship Pioneering Innovations Vii, Llc Rnai agents targeting fatty acid synthase and related methods
US12152052B2 (en) 2022-09-23 2024-11-26 Ionis Pharmaceuticals, Inc. Compounds and methods for reducing MECP2 expression
WO2025024334A1 (en) 2023-07-21 2025-01-30 Marrow Therapeutics, Inc. Hematopoietic cell targeting conjugates and related methods
WO2025024486A2 (en) 2023-07-25 2025-01-30 Flagship Pioneering Innovations Vii, Llc Cas endonucleases and related methods
WO2025024493A1 (en) 2023-07-25 2025-01-30 Flagship Pioneering Innovations Vii, Llc Cas endonucleases and related methods
WO2025068896A1 (en) 2023-09-26 2025-04-03 Astrazeneca Ab Compounds and methods for reducing psd3 expression
WO2025072331A1 (en) 2023-09-26 2025-04-03 Flagship Pioneering Innovations Vii, Llc Cas nucleases and related methods
WO2025117877A2 (en) 2023-12-01 2025-06-05 Flagship Pioneering Innovations Vii, Llc Cas nucleases and related methods
US12343357B2 (en) 2015-03-03 2025-07-01 Ionis Pharmaceuticals, Inc. Compositions and methods for modulating MECP2 expression
WO2025178854A2 (en) 2024-02-19 2025-08-28 Flagship Pioneering Innovations Vii, Llc Rnai agents targeting cideb and related methods
WO2025217275A2 (en) 2024-04-10 2025-10-16 Flagship Pioneering Innovations Vii, Llc Immune cell targeted compositions and related methods
WO2025252669A1 (en) 2024-06-03 2025-12-11 Evotec International Gmbh Modified oligonucleotides for reducing atxn3 expression
US12529055B2 (en) 2016-03-09 2026-01-20 Ionis Pharmaceuticals, Inc. Methods and compositions for inhibiting PMP22 expression
WO2026062247A1 (en) 2024-09-20 2026-03-26 Astrazeneca Ab Liquid-phase oligonucleotide synthesis using 2-(2-nitrophenyl)propyloxycarbonyl (nppoc) as a protecting group

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8957040B2 (en) 2010-02-08 2015-02-17 Isis Pharmaceuticals, Inc. Selective reduction of allelic variants
EP2673361B1 (en) * 2011-02-08 2016-04-13 Ionis Pharmaceuticals, Inc. Oligomeric compounds comprising bicyclic nucleotides and uses thereof
US10202599B2 (en) * 2011-08-11 2019-02-12 Ionis Pharmaceuticals, Inc. Selective antisense compounds and uses thereof
EP4291654A2 (en) 2021-02-12 2023-12-20 Alnylam Pharmaceuticals, Inc. Superoxide dismutase 1 (sod1) irna compositions and methods of use thereof for treating or preventing superoxide dismutase 1- (sod1-) associated neurodegenerative diseases
WO2023044412A1 (en) * 2021-09-17 2023-03-23 Ionis Pharmaceuticals, Inc. Compounds and methods for reducing dnm1l or drp1 expression
TW202328449A (zh) 2021-09-24 2023-07-16 美商艾拉倫製藥公司 微管相關蛋白ＴＡＵ（ＭＡＰＴ）ｉＲＮＡ試劑組合物及其使用方法
EP4441229A1 (en) * 2021-12-01 2024-10-09 Atalanta Therapeutics, Inc. Compositions and methods for treatment of epilepsies
EP4453215A2 (en) * 2021-12-22 2024-10-30 Ionis Pharmaceuticals, Inc. Compounds and methods for reducing glycogen synthase 1
US11879125B2 (en) 2022-03-16 2024-01-23 Empirico Inc. GalNAc compositions for improving siRNA bioavailability
AU2023245603A1 (en) 2022-03-28 2024-11-07 Empirico Inc. Modified oligonucleotides
AU2024301682A1 (en) * 2023-07-21 2026-01-22 Adarx Pharmaceuticals, Inc. Coagulation factor xi-modulating compositions and methods of use thereof
WO2025137143A2 (en) * 2023-12-21 2025-06-26 Aperture Therapeutics, Inc. Compositions for modulating cd33 expression
WO2025151406A1 (en) * 2024-01-08 2025-07-17 Denali Therapeutics Inc. Chemically modified oligonucleotides and conjugates and methods thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012170347A1 (en) * 2011-06-09 2012-12-13 Isis Pharmaceuticals, Inc. Bicyclic nucleosides and oligomeric compounds prepared therefrom
US8957200B2 (en) * 2010-06-07 2015-02-17 Isis Pharmaceuticals, Inc. Bicyclic nucleosides and oligomeric compounds prepared therefrom
US20160186175A1 (en) * 2014-12-30 2016-06-30 Ionis Pharmaceuticals, Inc. Bicyclic morpholino compounds and oligomeric compounds prepared therefrom
US20170044526A1 (en) * 2014-04-28 2017-02-16 Ionis Pharmaceuticals, Inc. Linkage modified oligomeric compounds
US20170327824A1 (en) * 2012-10-12 2017-11-16 Ionis Pharmaceuticals, Inc. Selective antisense compounds and uses thereof

Family Cites Families (157)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3687808A (en) 1969-08-14 1972-08-29 Univ Leland Stanford Junior Synthetic polynucleotides
US5367066A (en) 1984-10-16 1994-11-22 Chiron Corporation Oligonucleotides with selectably cleavable and/or abasic sites
FR2575751B1 (fr) 1985-01-08 1987-04-03 Pasteur Institut Nouveaux nucleosides de derives de l'adenosine, leur preparation et leurs applications biologiques
US4751219A (en) 1985-02-05 1988-06-14 Nederlandse Centrale Organisatie Voor Toegepast-Natuur-Wetenschappelijk Onderzoek Synthetic glycolipides, a process for the preparation thereof and several uses for these synthetic glycolipides
US5506337A (en) 1985-03-15 1996-04-09 Antivirals Inc. Morpholino-subunit combinatorial library and method
US5185444A (en) 1985-03-15 1993-02-09 Anti-Gene Deveopment Group Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages
US5034506A (en) 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
US5166315A (en) 1989-12-20 1992-11-24 Anti-Gene Development Group Sequence-specific binding polymers for duplex nucleic acids
EP0366685B1 (en) 1987-06-24 1994-10-19 Howard Florey Institute Of Experimental Physiology And Medicine Nucleoside derivatives
US5175273A (en) 1988-07-01 1992-12-29 Genentech, Inc. Nucleic acid intercalating agents
US5134066A (en) 1989-08-29 1992-07-28 Monsanto Company Improved probes using nucleosides containing 3-dezauracil analogs
US5130302A (en) 1989-12-20 1992-07-14 Boron Bilogicals, Inc. Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same
US5681941A (en) 1990-01-11 1997-10-28 Isis Pharmaceuticals, Inc. Substituted purines and oligonucleotide cross-linking
US5457191A (en) 1990-01-11 1995-10-10 Isis Pharmaceuticals, Inc. 3-deazapurines
US5459255A (en) 1990-01-11 1995-10-17 Isis Pharmaceuticals, Inc. N-2 substituted purines
US5587470A (en) 1990-01-11 1996-12-24 Isis Pharmaceuticals, Inc. 3-deazapurines
JPH0874B2 (ja) 1990-07-27 1996-01-10 アイシス・ファーマシューティカルス・インコーポレーテッド 遺伝子発現を検出および変調するヌクレアーゼ耐性、ピリミジン修飾オリゴヌクレオチド
US5432272A (en) 1990-10-09 1995-07-11 Benner; Steven A. Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases
US5948903A (en) 1991-01-11 1999-09-07 Isis Pharmaceuticals, Inc. Synthesis of 3-deazapurines
US5594121A (en) 1991-11-07 1997-01-14 Gilead Sciences, Inc. Enhanced triple-helix and double-helix formation with oligomers containing modified purines
US5484908A (en) 1991-11-26 1996-01-16 Gilead Sciences, Inc. Oligonucleotides containing 5-propynyl pyrimidines
TW393513B (en) 1991-11-26 2000-06-11 Isis Pharmaceuticals Inc Enhanced triple-helix and double-helix formation with oligomers containing modified pyrimidines
AU3222793A (en) 1991-11-26 1993-06-28 Gilead Sciences, Inc. Enhanced triple-helix and double-helix formation with oligomers containing modified pyrimidines
US5434257A (en) 1992-06-01 1995-07-18 Gilead Sciences, Inc. Binding compentent oligomers containing unsaturated 3',5' and 2',5' linkages
WO1994022890A1 (en) 1993-03-31 1994-10-13 Sterling Winthop Inc. Novel 5'-substituted nucleosides and oligomers produced therefrom
US5502177A (en) 1993-09-17 1996-03-26 Gilead Sciences, Inc. Pyrimidine derivatives for labeled binding partners
US5457187A (en) 1993-12-08 1995-10-10 Board Of Regents University Of Nebraska Oligonucleotides containing 5-fluorouracil
US5596091A (en) 1994-03-18 1997-01-21 The Regents Of The University Of California Antisense oligonucleotides comprising 5-aminoalkyl pyrimidine nucleotides
US5525711A (en) 1994-05-18 1996-06-11 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Pteridine nucleotide analogs as fluorescent DNA probes
US6172045B1 (en) 1994-12-07 2001-01-09 Neorx Corporation Cluster clearing agents
US6908903B1 (en) 1994-12-07 2005-06-21 Aletheon Pharmaceuticals, Inc. Cluster clearing agents
US20030119724A1 (en) 1995-11-22 2003-06-26 Ts`O Paul O.P. Ligands to enhance cellular uptake of biomolecules
CN1120707C (zh) 1995-11-22 2003-09-10 约翰斯·霍普金斯大学 增强生物分子的细胞摄取的配体
CN1231675A (zh) 1996-09-26 1999-10-13 味之素株式会社 修饰的生理活性蛋白及含有该蛋白的药物组合物
JP3756313B2 (ja) 1997-03-07 2006-03-15 武 今西 新規ビシクロヌクレオシド及びオリゴヌクレオチド類縁体
USRE44779E1 (en) 1997-03-07 2014-02-25 Santaris Pharma A/S Bicyclonucleoside and oligonucleotide analogues
US6770748B2 (en) 1997-03-07 2004-08-03 Takeshi Imanishi Bicyclonucleoside and oligonucleotide analogue
US6794499B2 (en) 1997-09-12 2004-09-21 Exiqon A/S Oligonucleotide analogues
US7572582B2 (en) 1997-09-12 2009-08-11 Exiqon A/S Oligonucleotide analogues
JP4236812B2 (ja) 1997-09-12 2009-03-11 エクシコン エ／エス オリゴヌクレオチド類似体
US6300319B1 (en) 1998-06-16 2001-10-09 Isis Pharmaceuticals, Inc. Targeted oligonucleotide conjugates
US7053207B2 (en) 1999-05-04 2006-05-30 Exiqon A/S L-ribo-LNA analogues
US6525191B1 (en) 1999-05-11 2003-02-25 Kanda S. Ramasamy Conformationally constrained L-nucleosides
US6383812B1 (en) 1999-05-28 2002-05-07 Academia Sinica Anti liver disease drug R-YEEE and method of synthesizing branched galactose-terminal glycoproteins
US8541548B2 (en) 1999-06-07 2013-09-24 Arrowhead Madison Inc. Compounds and methods for reversible modification of biologically active molecules
US20080281041A1 (en) 1999-06-07 2008-11-13 Rozema David B Reversibly Masked Polymers
US7491805B2 (en) 2001-05-18 2009-02-17 Sirna Therapeutics, Inc. Conjugates and compositions for cellular delivery
CN100406065C (zh) 2000-12-01 2008-07-30 细胞工厂治疗公司 糖基化/半乳糖基化肽、双官能接头和核苷酸单体/多聚体的缀合物以及相关的组合物和使用方法
WO2002087541A1 (en) 2001-04-30 2002-11-07 Protiva Biotherapeutics Inc. Lipid-based formulations for gene transfer
US20030175906A1 (en) 2001-07-03 2003-09-18 Muthiah Manoharan Nuclease resistant chimeric oligonucleotides
US20030158403A1 (en) 2001-07-03 2003-08-21 Isis Pharmaceuticals, Inc. Nuclease resistant chimeric oligonucleotides
US20100240730A1 (en) 2002-02-20 2010-09-23 Merck Sharp And Dohme Corp. RNA Interference Mediated Inhibition of Gene Expression Using Chemically Modified Short Interfering Nucleic Acid (siNA)
CA2498772A1 (en) 2002-09-11 2004-03-25 Santaris Pharma A/S Modified pna molecules
AU2003291755A1 (en) 2002-11-05 2004-06-07 Isis Pharmaceuticals, Inc. Oligomers comprising modified bases for binding cytosine and uracil or thymine and their use
WO2004041889A2 (en) 2002-11-05 2004-05-21 Isis Pharmaceuticals, Inc. Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation
US7723509B2 (en) 2003-04-17 2010-05-25 Alnylam Pharmaceuticals IRNA agents with biocleavable tethers
US7851615B2 (en) 2003-04-17 2010-12-14 Alnylam Pharmaceuticals, Inc. Lipophilic conjugated iRNA agents
ES2702942T3 (es) 2003-04-17 2019-03-06 Alnylam Pharmaceuticals Inc Agentes de ARNi modificados
WO2004101619A1 (ja) 2003-05-15 2004-11-25 Shionogi Co., Ltd. 機能的糖ペプチドの合理的設計および合成
WO2004106356A1 (en) 2003-05-27 2004-12-09 Syddansk Universitet Functionalized nucleotide derivatives
EP1661905B9 (en) 2003-08-28 2012-12-19 IMANISHI, Takeshi Novel artificial nucleic acids of n-o bond crosslinkage type
CA2538252C (en) 2003-09-18 2014-02-25 Isis Pharmaceuticals, Inc. 4'-thionucleosides and oligomeric compounds
EP1791567B1 (en) 2004-08-10 2015-07-29 Alnylam Pharmaceuticals Inc. Chemically modified oligonucleotides
US20090203132A1 (en) 2004-09-09 2009-08-13 Swayze Eric E Pyrrolidinyl groups for attaching conjugates to oligomeric compounds
US20060148740A1 (en) 2005-01-05 2006-07-06 Prosensa B.V. Mannose-6-phosphate receptor mediated gene transfer into muscle cells
US20080206869A1 (en) 2005-01-24 2008-08-28 Avaris Ab Nucleic Acid Complex
US7569686B1 (en) 2006-01-27 2009-08-04 Isis Pharmaceuticals, Inc. Compounds and methods for synthesis of bicyclic nucleic acid analogs
WO2007090071A2 (en) 2006-01-27 2007-08-09 Isis Pharmaceuticals, Inc. 6-modified bicyclic nucleic acid analogs
US7666854B2 (en) 2006-05-11 2010-02-23 Isis Pharmaceuticals, Inc. Bis-modified bicyclic nucleic acid analogs
AU2007249349B2 (en) 2006-05-11 2012-03-08 Isis Pharmaceuticals, Inc. 5'-Modified bicyclic nucleic acid analogs
US8658211B2 (en) 2006-08-18 2014-02-25 Arrowhead Madison Inc. Polyconjugates for in vivo delivery of polynucleotides
CN101500548A (zh) 2006-08-18 2009-08-05 弗·哈夫曼-拉罗切有限公司 用于体内递送多核苷酸的多缀合物
ES2526295T5 (es) 2006-10-18 2021-05-04 Ionis Pharmaceuticals Inc Compuestos antisentido
WO2008101157A1 (en) 2007-02-15 2008-08-21 Isis Pharmaceuticals, Inc. 5'-substituted-2'-f modified nucleosides and oligomeric compounds prepared therefrom
US9216228B2 (en) 2007-02-16 2015-12-22 KTB Tumorforschungsgesellschaft MBM Receptor and antigen targeted prodrug
CA2685127C (en) 2007-04-23 2019-01-08 Alnylam Pharmaceuticals, Inc. Glycoconjugates of rna interference agents
CA2688321A1 (en) 2007-05-30 2008-12-11 Isis Pharmaceuticals, Inc. N-substituted-aminomethylene bridged bicyclic nucleic acid analogs
DK2173760T4 (en) 2007-06-08 2016-02-08 Isis Pharmaceuticals Inc Carbocyclic bicyclic nukleinsyreanaloge
AU2008272918B2 (en) 2007-07-05 2012-09-13 Isis Pharmaceuticals, Inc. 6-disubstituted bicyclic nucleic acid analogs
KR101654007B1 (ko) 2007-08-15 2016-09-05 아이오니스 파마수티컬즈, 인코포레이티드 테트라하이드로피란 핵산 유사체
WO2009067647A1 (en) 2007-11-21 2009-05-28 Isis Pharmaceuticals, Inc. Carbocyclic alpha-l-bicyclic nucleic acid analogs
WO2009073809A2 (en) 2007-12-04 2009-06-11 Alnylam Pharmaceuticals, Inc. Carbohydrate conjugates as delivery agents for oligonucleotides
CA2713379A1 (en) 2008-01-31 2009-11-05 Alnylam Pharmaceuticals, Inc. Optimized methods for delivery of dsrna targeting the pcsk9 gene
WO2009100320A2 (en) 2008-02-07 2009-08-13 Isis Pharmaceuticals, Inc. Bicyclic cyclohexitol nucleic acid analogs
US20110130440A1 (en) 2008-03-26 2011-06-02 Alnylam Pharmaceuticals, Inc. Non-natural ribonucleotides, and methods of use thereof
CA2721183C (en) 2008-04-11 2019-07-16 Alnylam Pharmaceuticals, Inc. Site-specific delivery of nucleic acids by combining targeting ligands with endosomolytic components
AU2009298802A1 (en) 2008-09-23 2010-04-08 Alnylam Pharmaceuticals, Inc. Chemical modifications of monomers and oligonucleotides with cycloaddition
DK2356129T3 (da) 2008-09-24 2013-05-13 Isis Pharmaceuticals Inc Substituerede alpha-L-bicykliske nukleosider
CN111808084A (zh) 2008-11-10 2020-10-23 阿布特斯生物制药公司 用于递送治疗剂的新型脂质和组合物
EP3243504A1 (en) 2009-01-29 2017-11-15 Arbutus Biopharma Corporation Improved lipid formulation
SG10201911942UA (en) 2009-05-05 2020-02-27 Muthiah Manoharan Lipid compositions
KR101766408B1 (ko) 2009-06-10 2017-08-10 알닐람 파마슈티칼스 인코포레이티드 향상된 지질 조성물
JP5894913B2 (ja) 2009-06-15 2016-03-30 アルナイラム ファーマシューティカルズ， インコーポレイテッドＡｌｎｙｌａｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． Ｐｃｓｋ９遺伝子を標的とする、脂質で製剤化されたｄｓｒｎａ
US9012421B2 (en) 2009-08-06 2015-04-21 Isis Pharmaceuticals, Inc. Bicyclic cyclohexose nucleic acid analogs
TWI458493B (zh) 2009-09-25 2014-11-01 Iner Aec Executive Yuan 新穎肝標靶藥劑與合成方法
TWI388338B (zh) 2009-10-26 2013-03-11 Iner Aec Executive Yuan 對聚合醣鏈進行放射標誌以作為肝受體造影劑之方法
TWI391144B (zh) 2009-10-26 2013-04-01 Iner Aec Executive Yuan 一種定量肝殘餘功能的檢驗方法與其新穎肝受體造影檢驗藥劑
WO2011072290A2 (en) 2009-12-11 2011-06-16 The Regents Of The University Of Michigan Targeted dendrimer-drug conjugates
US9198972B2 (en) 2010-01-28 2015-12-01 Alnylam Pharmaceuticals, Inc. Monomers and oligonucleotides comprising cycloaddition adduct(s)
SI2539451T1 (sl) 2010-02-24 2016-04-29 Arrowhead Research Corporation Sestavki za ciljano dostavo sirna
US20130109817A1 (en) 2010-03-26 2013-05-02 Mersana Therapeutics, Inc. Modified Polymers for Delivery of Polynucleotides, Method of Manufacture, and Methods of Use Thereof
EP2553019A1 (en) 2010-03-26 2013-02-06 Mersana Therapeutics, Inc. Modified polymers for delivery of polynucleotides, method of manufacture, and methods of use thereof
US9102938B2 (en) 2010-04-01 2015-08-11 Alnylam Pharmaceuticals, Inc. 2′ and 5′ modified monomers and oligonucleotides
US10913767B2 (en) 2010-04-22 2021-02-09 Alnylam Pharmaceuticals, Inc. Oligonucleotides comprising acyclic and abasic nucleosides and analogs
US20130236968A1 (en) 2010-06-21 2013-09-12 Alnylam Pharmaceuticals, Inc. Multifunctional copolymers for nucleic acid delivery
CA2812046A1 (en) 2010-09-15 2012-03-22 Alnylam Pharmaceuticals, Inc. Modified irna agents
WO2012068187A1 (en) 2010-11-19 2012-05-24 Merck Sharp & Dohme Corp. Poly(amide) polymers for the delivery of oligonucleotides
US8501930B2 (en) 2010-12-17 2013-08-06 Arrowhead Madison Inc. Peptide-based in vivo siRNA delivery system
AU2011343664B2 (en) 2010-12-17 2015-10-08 Arrowhead Pharmaceuticals, Inc. Galactose cluster-pharmacokinetic modulator targeting moiety for siRNA
CA3131967A1 (en) 2010-12-29 2012-07-05 F. Hoffman-La Roche Ag Small molecule conjugates for intracellular delivery of nucleic acids
EP2673361B1 (en) 2011-02-08 2016-04-13 Ionis Pharmaceuticals, Inc. Oligomeric compounds comprising bicyclic nucleotides and uses thereof
RS61447B1 (sr) 2011-04-21 2021-03-31 Glaxo Group Ltd Modulacija ekspresije virusa hepatitisa b (hbv)
MX390699B (es) 2011-06-21 2025-03-21 Alnylam Pharmaceuticals Inc Composiciones y metodos para inhibicion de genes para apolipoproteina c-iii (apoc3).
US10202599B2 (en) 2011-08-11 2019-02-12 Ionis Pharmaceuticals, Inc. Selective antisense compounds and uses thereof
WO2013032829A1 (en) 2011-08-26 2013-03-07 Arrowhead Research Corporation Poly(vinyl ester) polymers for in vivo nucleic acid delivery
WO2013033230A1 (en) 2011-08-29 2013-03-07 Isis Pharmaceuticals, Inc. Oligomer-conjugate complexes and their use
EP3730618A1 (en) 2011-11-18 2020-10-28 Alnylam Pharmaceuticals, Inc. Rnai agents, compositions and methods of use thereof for treating transthyretin (ttr) associated diseases
US9243291B1 (en) * 2011-12-01 2016-01-26 Isis Pharmaceuticals, Inc. Methods of predicting toxicity
WO2013159108A2 (en) 2012-04-20 2013-10-24 Isis Pharmaceuticals, Inc. Oligomeric compounds comprising bicyclic nucleotides and uses thereof
US20150299696A1 (en) 2012-05-02 2015-10-22 Sirna Therapeutics, Inc. SHORT INTERFERING NUCLEIC ACID (siNA) COMPOSITIONS
TW201808342A (zh) 2012-05-02 2018-03-16 喜納製藥公司 包含四ｇａｌｎａｃ之新穎結合物及傳送寡核苷酸之方法
EP4052709A1 (en) 2012-10-11 2022-09-07 Ionis Pharmaceuticals, Inc. Methods of treating kennedy's disease
AR092982A1 (es) 2012-10-11 2015-05-13 Isis Pharmaceuticals Inc Modulacion de la expresion de receptores androgenicos
US9695418B2 (en) 2012-10-11 2017-07-04 Ionis Pharmaceuticals, Inc. Oligomeric compounds comprising bicyclic nucleosides and uses thereof
EP2906255B1 (en) 2012-10-12 2023-02-22 Ionis Pharmaceuticals, Inc. Antisense compounds and uses thereof
DK2992098T3 (da) 2013-05-01 2019-06-17 Ionis Pharmaceuticals Inc Sammensætninger og fremgangsmåder til modulering af hbv- og ttr-ekspression
TW201536329A (zh) 2013-08-09 2015-10-01 Isis Pharmaceuticals Inc 用於調節失養性肌強直蛋白質激酶(dmpk)表現之化合物及方法
US10119136B2 (en) 2014-01-09 2018-11-06 Alnylam Pharmaceuticals, Inc. RNAi agents modified at the 4′-C position
US10208947B2 (en) 2014-03-26 2019-02-19 Rockwell Automation Technologies, Inc. Cloud-level analytics for boiler networks
US11077132B2 (en) 2015-02-04 2021-08-03 F. Hoffmann-La Roche Ag Tau antisense oligomers and uses thereof
CN115181778A (zh) 2015-02-04 2022-10-14 百时美施贵宝公司 选择治疗性分子的方法
WO2016127002A1 (en) 2015-02-04 2016-08-11 Bristol-Myers Squibb Company Lna oligonucleotides with alternating flanks
AU2016222546B2 (en) 2015-02-26 2020-01-23 Ionis Pharmaceuticals, Inc. Allele specific modulators of P23H rhodopsin
MX2017012426A (es) 2015-04-03 2018-01-26 Ionis Pharmaceuticals Inc Composiciones y metodos para modular la expresion de tmprss6.
IL320434A (en) 2015-07-22 2025-06-01 Wave Life Sciences Ltd Oligonucleotide preparations and methods
CN108513588A (zh) 2015-09-24 2018-09-07 Ionis制药公司 Kras表达的调节剂
LT3374509T (lt) 2015-11-12 2021-03-10 F. Hoffmann-La Roche Ag Oligonukleotidai, skirti sukelti iš tėvo paveldėto ube3a raišką
JP7012033B2 (ja) 2016-06-17 2022-02-10 エフ．ホフマン－ラ ロシュ アーゲー インビトロ腎毒性スクリーニングアッセイ
CN109328236B (zh) 2016-06-17 2022-10-25 豪夫迈·罗氏有限公司 体外肾毒性筛选测定法
MX2018015722A (es) 2016-07-01 2019-05-27 Hoffmann La Roche Oligonucleotidos antisentido para modular expresion del requisito de alta temperatura a 1 (htra1).
US11180756B2 (en) 2017-03-09 2021-11-23 Ionis Pharmaceuticals Morpholino modified oligomeric compounds
US20190055564A1 (en) 2017-06-01 2019-02-21 F. Hoffmann-La Roche Ag Antisense oligonucleotides for modulating htra1 expression
EP3664816A4 (en) 2017-08-08 2021-05-19 Wave Life Sciences Ltd. OLIGONUCLEOTIDE COMPOSITIONS AND RELATED PROCESSES
CN111511914B (zh) * 2017-10-16 2023-11-17 豪夫迈·罗氏有限公司 减少PAPD5和PAPD7 mRNA的核酸分子用于治疗乙型肝炎感染
SG11202006528XA (en) 2018-01-12 2020-08-28 Bristol Myers Squibb Co Antisense oligonucleotides targeting alpha-synuclein and uses thereof
SG11202006142PA (en) 2018-01-12 2020-07-29 Roche Innovation Ct Copenhagen As Alpha-synuclein antisense oligonucleotides and uses thereof
CN120310791A (zh) 2018-01-12 2025-07-15 百时美施贵宝公司 靶向α-突触核蛋白的反义寡核苷酸及其用途
WO2019157531A1 (en) 2018-02-12 2019-08-15 Ionis Pharmaceuticals, Inc. Modified compounds and uses thereof
TWI840345B (zh) 2018-03-02 2024-05-01 美商Ionis製藥公司 Irf4表現之調節劑
SG11202008660TA (en) 2018-04-11 2020-10-29 Ionis Pharmaceuticals Inc Modulators of ezh2 expression
WO2019245957A1 (en) 2018-06-18 2019-12-26 Ionis Pharmaceuticals, Inc. Linkage modified oligomeric compounds
PE20210346A1 (es) 2018-07-03 2021-02-25 Hoffmann La Roche Oligonucleotidos para modular la expresion de tau
CN113423385A (zh) 2019-02-01 2021-09-21 波涛生命科学有限公司 寡核苷酸组合物及其方法
EP3947677A1 (en) 2019-04-04 2022-02-09 F. Hoffmann-La Roche AG Oligonucleotides for modulating atxn2 expression
SG11202111387YA (en) 2019-04-25 2021-11-29 Wave Life Sciences Ltd Oligonucleotide compositions and methods of use thereof
EP3965780A4 (en) 2019-05-09 2023-10-25 Wave Life Sciences Ltd. OLIGONUCLEOTIDE COMPOSITIONS AND METHODS OF USE
CN113950529A (zh) 2019-06-06 2022-01-18 豪夫迈·罗氏有限公司 靶向atxn3的反义寡核苷酸

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8957200B2 (en) * 2010-06-07 2015-02-17 Isis Pharmaceuticals, Inc. Bicyclic nucleosides and oligomeric compounds prepared therefrom
WO2012170347A1 (en) * 2011-06-09 2012-12-13 Isis Pharmaceuticals, Inc. Bicyclic nucleosides and oligomeric compounds prepared therefrom
US20170327824A1 (en) * 2012-10-12 2017-11-16 Ionis Pharmaceuticals, Inc. Selective antisense compounds and uses thereof
US20170044526A1 (en) * 2014-04-28 2017-02-16 Ionis Pharmaceuticals, Inc. Linkage modified oligomeric compounds
US20160186175A1 (en) * 2014-12-30 2016-06-30 Ionis Pharmaceuticals, Inc. Bicyclic morpholino compounds and oligomeric compounds prepared therefrom

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3752612A4 *

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12343357B2 (en) 2015-03-03 2025-07-01 Ionis Pharmaceuticals, Inc. Compositions and methods for modulating MECP2 expression
US12529055B2 (en) 2016-03-09 2026-01-20 Ionis Pharmaceuticals, Inc. Methods and compositions for inhibiting PMP22 expression
US11332733B2 (en) 2018-02-12 2022-05-17 lonis Pharmaceuticals, Inc. Modified compounds and uses thereof
US12234447B2 (en) 2018-02-12 2025-02-25 Ionis Pharmaceuticals, Inc. Modified compounds and uses thereof
US11149264B2 (en) 2018-02-12 2021-10-19 Ionis Pharmaceuticals, Inc. Modified compounds and uses thereof
US11359199B2 (en) 2019-03-20 2022-06-14 President And Fellows Of Harvard College Antisense oligonucleotide-based progranulin augmentation therapy in neurodegenerative diseases
US12595479B2 (en) 2019-03-20 2026-04-07 President And Fellows Of Harvard College Antisense oligonucleotide-based progranulin augmentation therapy in neurodegenerative diseases
EP4660307A2 (en) 2019-07-26 2025-12-10 Ionis Pharmaceuticals, Inc. Compounds and methods for modulating gfap
WO2021021673A1 (en) 2019-07-26 2021-02-04 Ionis Pharmaceuticals, Inc. Compounds and methods for modulating gfap
US11629348B2 (en) 2019-08-15 2023-04-18 Ionis Pharmaceuticals, Inc. Linkage modified oligomeric compounds and uses thereof
US12595482B2 (en) 2019-08-15 2026-04-07 Ionis Pharmaceuticals, Inc. Linkage modified oligomeric compounds and uses thereof
WO2021084495A1 (en) 2019-11-01 2021-05-06 Novartis Ag The use of a splicing modulator for a treatment slowing progression of huntington's disease
WO2021202788A3 (en) * 2020-04-03 2021-11-11 Ionis Pharmaceuticals, Inc. Modified oligomeric compounds and uses thereof
JP2023527330A (ja) * 2020-05-28 2023-06-28 コロ バイオ， インコーポレイテッド Ｓｅｒｐｉｎａ１のａｄａｒ媒介編集のための方法及び組成物
JP2023530072A (ja) * 2020-06-19 2023-07-13 アイオーニス ファーマシューティカルズ， インコーポレーテッド Ｐｍｐ２２を調節するための化合物及び方法
EP4168549A4 (en) * 2020-06-19 2024-10-09 Ionis Pharmaceuticals, Inc. COMPOUNDS AND METHODS FOR PMP22 MODULATION
EP4488371A3 (en) * 2020-11-18 2025-04-09 Ionis Pharmaceuticals, Inc. Compounds and methods for modulating angiotensinogen expression
EP4136092A4 (en) * 2020-11-18 2023-10-11 Ionis Pharmaceuticals, Inc. COMPOUNDS AND METHODS FOR MODULATING ANGIOTENSINOGEN EXPRESSION
US11447521B2 (en) 2020-11-18 2022-09-20 Ionis Pharmaceuticals, Inc. Compounds and methods for modulating angiotensinogen expression
EP4488371A2 (en) 2020-11-18 2025-01-08 Ionis Pharmaceuticals, Inc. Compounds and methods for modulating angiotensinogen expression
JP7820374B2 (ja) 2020-11-18 2026-02-25 アイオーニス ファーマシューティカルズ， インコーポレーテッド アンジオテンシノーゲン発現を調節するための化合物及び方法
JP2023549563A (ja) * 2020-11-18 2023-11-27 アイオーニス ファーマシューティカルズ， インコーポレーテッド アンジオテンシノーゲン発現を調節するための化合物及び方法
US20240336915A1 (en) * 2021-01-22 2024-10-10 Ionis Pharmaceuticals, Inc. Compounds and methods for reducing dux4 expression
WO2022208170A1 (en) 2021-03-29 2022-10-06 Novartis Ag The use of the splicing modulator brataplam for slowing progression of huntington's disease
WO2022266414A1 (en) * 2021-06-18 2022-12-22 Ionis Pharmaceuticals, Inc. Compounds and methods for reducing ifnar1 expression
US11753644B2 (en) 2021-06-18 2023-09-12 Ionis Pharmaceuticals, Inc. Compounds and methods for reducing IFNAR1 expression
WO2023075766A1 (en) * 2021-10-27 2023-05-04 Wave Life Sciences Ltd. Oligonucleotide compositions and methods of use thereof
US12152052B2 (en) 2022-09-23 2024-11-26 Ionis Pharmaceuticals, Inc. Compounds and methods for reducing MECP2 expression
WO2024220746A2 (en) 2023-04-21 2024-10-24 Flagship Pioneering Innovations Vii, Llc Rnai agents targeting fatty acid synthase and related methods
WO2025024334A1 (en) 2023-07-21 2025-01-30 Marrow Therapeutics, Inc. Hematopoietic cell targeting conjugates and related methods
WO2025024493A1 (en) 2023-07-25 2025-01-30 Flagship Pioneering Innovations Vii, Llc Cas endonucleases and related methods
WO2025024486A2 (en) 2023-07-25 2025-01-30 Flagship Pioneering Innovations Vii, Llc Cas endonucleases and related methods
WO2025072331A1 (en) 2023-09-26 2025-04-03 Flagship Pioneering Innovations Vii, Llc Cas nucleases and related methods
WO2025068896A1 (en) 2023-09-26 2025-04-03 Astrazeneca Ab Compounds and methods for reducing psd3 expression
WO2025117877A2 (en) 2023-12-01 2025-06-05 Flagship Pioneering Innovations Vii, Llc Cas nucleases and related methods
WO2025178854A2 (en) 2024-02-19 2025-08-28 Flagship Pioneering Innovations Vii, Llc Rnai agents targeting cideb and related methods
WO2025217275A2 (en) 2024-04-10 2025-10-16 Flagship Pioneering Innovations Vii, Llc Immune cell targeted compositions and related methods
WO2025252669A1 (en) 2024-06-03 2025-12-11 Evotec International Gmbh Modified oligonucleotides for reducing atxn3 expression
WO2026062247A1 (en) 2024-09-20 2026-03-26 Astrazeneca Ab Liquid-phase oligonucleotide synthesis using 2-(2-nitrophenyl)propyloxycarbonyl (nppoc) as a protecting group

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CA3090901A1 (en) 2019-08-15
US12234447B2 (en) 2025-02-25
US20210261945A1 (en) 2021-08-26
AU2019218987B2 (en) 2025-04-24
US11332733B2 (en) 2022-05-17
JP7317029B2 (ja) 2023-07-28
US20210017513A1 (en) 2021-01-21
EP3752612A1 (en) 2020-12-23
AU2019218987A1 (en) 2020-07-23
US20230068063A1 (en) 2023-03-02

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