Compounds and methods for reducing nlrp3 expression
AssigneeIonis Pharmaceuticals, Inc.
InventorsSusan M. FREIER, Huynh-Hoa BUI
Life of this patent
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Abstract
Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of NLRP3 RNA in a cell or subject, and in certain instances reducing the amount of NLRP3 protein in a cell or subject. These compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom of a kidney injury or kidney disease, including acute kidney injury and chronic kidney disease. The compounds, methods, and pharmaceutical compositions are further useful in the treatment of a cardiac disorder or cardiac injury.
Claims85
An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 50, 12 to 45, 12 to 40, 12 to 35, 12 to 30, 12 to 25, or 12 to 20 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to an equal length portion of a NLRP3 nucleic acid, and wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobases complementary to an equal length portion of the nucleobase sequence of any one of SEQ ID NOs:
- 20-2799.
An oligomeric compound comprising a modified oligonucleotide, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary, at least 85% complementary, at least 90% complementary, or at least 95% complementary to an equal length portion within any of nucleobases 12138-12155, 14478-14523, 14578-14622, 14667-14693, 15111-15130, 15182-15200, 17668-17686, 20272-20291, 20634-20657, 23475-23512, or 25026-25049 of SEQ ID NO:
- 1.
An oligomeric compound comprising a modified oligonucleotide consisting of 16 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence of SEQ ID NO:
- 1454.
An oligomeric compound comprising a modified oligonucleotide consisting of 16 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence of SEQ ID NO:
- 628.
An oligomeric compound comprising a modified oligonucleotide consisting of 16 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence of SEQ ID NO:
- 178.
An oligomeric compound comprising a modified oligonucleotide consisting of 16 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence of SEQ ID NO:
- 420.
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 notation:
- AksAksmCksTdsAdsTdsTdsAdsAdsGdsmCdsAdsAdsmCksGksGk (SEQ ID NO:
- 628);
- 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′43-D-deoxyribosyl sugar moiety, and
- s=a phosphorothioate internucleoside linkage.
A modified oligonucleotide according to the following chemical notation:
- TksGksGksAdsAdsTdsAdsTdsAdsTdsmCdsGdsAdsGksmCksAk (SEQ ID NO:
- 1454);
- 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′43-D-deoxyribosyl sugar moiety, and
- s=a phosphorothioate internucleoside linkage.
A modified oligonucleotide according to the following chemical notation:
- mCksmCesTksTasTasTasmCdsGasAdsAdsTasTasTesGesmCksmCk (SEQ ID NO:
- 420);
- 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,
- e=a 2′-MOE β-D-ribosyl sugar moiety,
- d=a 2′43-D-deoxyribosyl sugar moiety, and
- s=a phosphorothioate internucleoside linkage.
Dependencies are inferred from the claim text.