Compounds and methods for reducing pln expression
AssigneeIonis Pharmaceuticals, Inc.
InventorsAdam MULLICK, Huynh-Hoa BUI, Susan M. FREIER, Ting Yuan YEH, Dieter KUBLI
Life of this patent
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Abstract
Provided are oligomeric agents, oligomeric compounds, methods, and pharmaceutical compositions for reducing the amount or activity of PLN RNA in a cell or animal, and in certain instances reducing the amount of PLN protein in a cell or animal. Such oligomeric agents, oligomeric compounds, methods, and pharmaceutical compositions are useful to treat cardiomyopathy, heart failure, or arrhythmia.
Claims180
An oligomeric compound comprising a modified oligonucleotide consisting of 8 to 80 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to an equal length portion of a PLN nucleic acid, and wherein the modified oligonucleotide has at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
An oligomeric compound, wherein the oligomeric compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases of any of the nucleobase sequences of any of SEQ ID NOs:
- 15-1712.
An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
- mCksmCksAksTdsAdsmCdsTdsTdsGdsAdsTdsTdsmCdsTksmCksAk (SEQ ID NO:
- 185), wherein:
- A=an adenine nucleobase,
- mC=a 5-methyl cytosine nucleobase,
- G=a guanine nucleobase,
- T=a thymine nucleobase,
- k=a cEt modified sugar moiety,
- d=a 2′-β-D-deoxyribosyl sugar moiety, and
- s=a phosphorothioate internucleoside linkage.
An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
- GksTksAksGdsTdsTdsAdsAdsGdsAdsTdsTdsTdsTksGksmCk (SEQ ID NO:
- 752), wherein:
- A=an adenine nucleobase,
- mC=a 5-methyl cytosine nucleobase,
- G=a guanine nucleobase,
- T=a thymine nucleobase,
- k=a cEt modified sugar moiety,
- d=a 2′-β-D-deoxyribosyl sugar moiety, and
- s=a phosphorothioate internucleoside linkage.
An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
- AksmCksAksmCdsGdsAdsGdsTdsAdsTdsAdsTdsTdsAksGksGk (SEQ ID NO:
- 609), wherein:
- A=an adenine nucleobase,
- mC=a 5-methyl cytosine nucleobase,
- G=a guanine nucleobase,
- T=a thymine nucleobase,
- k=a cEt modified sugar moiety,
- d=a 2′-β-D-deoxyribosyl sugar moiety, and
- s=a phosphorothioate internucleoside linkage.
An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
- AksAksGdsAdsTdsAdsTdsAdsGdsTdsAdsTksGesGksTesAk (SEQ ID NO:
- 45), wherein:
- A=an adenine nucleobase,
- G=a guanine nucleobase,
- T=a thymine nucleobase,
- e=a 2′-MOE sugar moiety,
- k=a cEt modified sugar moiety
- d=a 2′-β-D-deoxyribosyl sugar moiety, and
- s=a phosphorothioate internucleoside linkage.
An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
- AksmCksGdsAdsGdsTdsAdsTdsAdsTdsTdsAksGesGksAesAk (SEQ ID NO:
- 737), wherein:
- A=an adenine nucleobase,
- mC=a 5-methyl cytosine nucleobase,
- G=a guanine nucleobase,
- T=a thymine nucleobase,
- e=a 2′-MOE sugar moiety,
- k=a cEt modified sugar moiety
- d=a 2′-β-D-deoxyribosyl sugar moiety, and
- s=a phosphorothioate internucleoside linkage.
An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
- AksAksAdsGdsAdsTdsAdsTdsAdsGdsTdsAksTesGksGesTk (SEQ ID NO:
- 120), wherein:
- A=an adenine nucleobase,
- G=a guanine nucleobase,
- T=a thymine nucleobase,
- e=a 2′-MOE sugar moiety,
- k=a cEt modified sugar moiety
- d=a 2′-β-D-deoxyribosyl sugar moiety, and
- s=a phosphorothioate internucleoside linkage.
An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
- mCksAksmCksGdsAdsGdsTdsAdsTdsAdsTdsTdsAksGksGksAe (SEQ ID NO:
- 675), wherein:
- A=an adenine nucleobase,
- mC=a 5-methyl cytosine nucleobase,
- G=a guanine nucleobase,
- T=a thymine nucleobase,
- e=a 2′-MOE sugar moiety,
- k=a cEt modified sugar moiety
- d=a 2′-β-D-deoxyribosyl sugar moiety, and
- s=a phosphorothioate internucleoside linkage.
An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
- [C16-HA]oAksAksGdsAdsTdsAdsTdsAdsGdsTdsAdsTksGesGksTesAk (SEQ ID NO:
- 45), wherein:
- A=an adenine nucleobase,
- G=a guanine nucleobase,
- T=a thymine nucleobase,
- e=a 2′-MOE sugar moiety,
- k=a cEt modified sugar moiety
- d=a 2′-β-D-deoxyribosyl sugar moiety,
- o=a phosphodiester linkage,
- s=a phosphorothioate internucleoside linkage, and
An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
- [C16-HA]oAksmCksAksmCdsGdsAdsGdsTdsAdsTdsAdsTdsTdsAksGksGk (SEQ ID NO:
- 609), wherein:
- A=an adenine nucleobase,
- mC=a 5-methyl cytosine nucleobase,
- G=a guanine nucleobase,
- T=a thymine nucleobase,
- k=a cEt modified sugar moiety
- d=a 2′-β-D-deoxyribosyl sugar moiety,
- o=a phosphodiester linkage,
- s=a phosphorothioate internucleoside linkage, and
An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
- [C16-HA]oGksTksAksGdsTdsTdsAdsAdsGdsAdsTdsTdsTdsTksGksmCk (SEQ ID NO:
- 752), wherein:
- A=an adenine nucleobase,
- mC=a 5-methyl cytosine nucleobase,
- G=a guanine nucleobase,
- T=a thymine nucleobase,
- k=a cEt modified sugar moiety
- d=a 2′-β-D-deoxyribosyl sugar moiety,
- o=a phosphodiester linkage,
- s=a phosphorothioate internucleoside linkage, and
An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
- [C16-HA]oAksAksAdsGdsAdsTdsAdsTdsAdsGdsTdsAksTesGksGesTk (SEQ ID NO:
- 120), wherein:
- A=an adenine nucleobase,
- G=a guanine nucleobase,
- T=a thymine nucleobase,
- e=a 2′-MOE sugar moiety,
- k=a cEt modified sugar moiety
- d=a 2′-β-D-deoxyribosyl sugar moiety,
- o=a phosphodiester linkage,
- s=a phosphorothioate internucleoside linkage, and
An oligomeric compound according to the following chemical structure:
An oligomeric compound according to the following chemical structure:
- or a salt thereof.
An oligomeric compound according to the following chemical structure:
An oligomeric compound according to the following chemical structure:
- or a salt thereof.
An oligomeric compound according to the following chemical structure:
An oligomeric compound according to the following chemical structure:
- or a salt thereof.
An oligomeric compound according to the following chemical structure:
An oligomeric compound according to the following chemical structure:
- or a salt thereof.
A modified oligonucleotide according to the following chemical structure:
A modified oligonucleotide according to the following chemical structure:
- or a salt thereof.
A modified oligonucleotide according to the following chemical structure:
A modified oligonucleotide according to the following chemical structure:
- or a salt thereof.
A modified oligonucleotide according to the following chemical structure:
A modified oligonucleotide according to the following chemical structure:
- or a salt thereof.
A modified oligonucleotide according to the following chemical structure:
A modified oligonucleotide according to the following chemical structure:
- or a salt thereof.
A modified oligonucleotide according to the following chemical structure:
A modified oligonucleotide according to the following chemical structure:
- or a salt thereof.
A modified oligonucleotide according to the following chemical structure:
A modified oligonucleotide according to the following chemical structure:
- or a salt thereof.
A modified oligonucleotide according to the following chemical structure:
A modified oligonucleotide according to the following chemical structure:
- or a salt thereof.
An oligomeric duplex comprising:
- a first oligomeric compound comprising a first modified oligonucleotide consisting of 19 to 29 linked nucleosides wherein the nucleobase sequence of the first modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 contiguous nucleobases of the nucleobase sequence of any of SEQ ID NOs:
- 1713-2024;
- and
- a second oligomeric compound comprising a second modified oligonucleotide consisting of 15 to 29 linked nucleosides wherein the nucleobase sequence of the second modified oligonucleotide comprises a complementary region of at least 8 nucleobases that is at least 90% complementary to an equal length portion of the first modified oligonucleotide.
An oligomeric duplex comprising:
- a first oligomeric compound comprising a first modified oligonucleotide consisting of 19 to 29 linked nucleosides wherein the nucleobase sequence of the first modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 contiguous nucleobases of the nucleobase sequence of any of SEQ ID NOs:
- 1713-2024;
- and
- a second oligomeric compound comprising a second modified oligonucleotide consisting of 15 to 29 linked nucleosides wherein the nucleobase sequence of the second modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases of the nucleobase sequence of any of SEQ ID NOs:
- 2025-2336, wherein the nucleobase sequence of the second modified oligonucleotide is at least 90% complementary to an equal length portion of the first modified oligonucleotide.
An oligomeric duplex comprising:
- a first oligomeric compound comprising a first modified oligonucleotide consisting of 23 linked nucleosides wherein the nucleobase sequence of the first modified oligonucleotide comprises or consists of the nucleobase sequence of any of SEQ ID NOs:
- 1713-2024;
- and
- a second oligomeric compound comprising a second modified oligonucleotide consisting of 21 linked nucleosides wherein the nucleobase sequence of the second modified oligonucleotide comprises or consists of the nucleobase sequence of any of SEQ ID NOs:
- 2025-2336, wherein the nucleobase sequence of the second modified oligonucleotide is at least 90% complementary to an equal length portion of the first modified oligonucleotide.
Dependencies are inferred from the claim text.