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Patexia Research
Patent No. US 11180757
Issue Date Nov 23, 2021
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Patent 11180757 - 17b-hydroxysteroid dehydrogenase type 13 (HSD17B13) iRNA compositions and methods of use thereof > Claims

  • 1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13) in a cell, comprising a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides which differ by no more than three nucleotides from SEQ ID NO: 4498, and the antisense strand comprises a region of complementarity to at least 15 contiguous nucleotides differing by no more than three nucleotides from nucleotides 2242-2264 of SEQ ID NO: 1,wherein at least one of the nucleotides of the sense strand and at least one of the nucleotides of the antisense strand comprises a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoro modification.
    • 2. The dsRNA agent of claim 1, wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified.
    • 3. The dsRNA agent of claim 1, wherein the sense strand comprises no more than four 2′-fluoro modified nucleotides.
    • 4. The dsRNA agent of claim 1, wherein the antisense strand comprises no more than six 2′-fluoro modified nucleotides.
    • 5. The dsRNA agent of claim 1, wherein the antisense strand comprises at least one glycol-modified nucleotide.
      • 6. The dsRNA agent of claim 5, wherein the antisense strand comprises a glycol modified nucleotide at position 7, counting from the 5′-end.
    • 7. The dsRNA agent of claim 1, wherein the sense strand comprises four 2′-fluoro modified nucleotides at nucleotides 7 and 9-11, counting from the 5′-end, and wherein the antisense strand comprises three 2′-fluoro modified nucleotides at nucleotides 2, 14, and 16, counting from the 5′-end, and one glycol modified nucleotide at nucleotide 7, counting from the 5′-end.
    • 8. The dsRNA agent of claim 1, wherein: (a) the sense strand comprises at least one phosphorothioate or methylphosphonate internucleotide linkage; (b) the antisense strand comprises at least one phosphorothioate or methylphosphonate internucleotide linkage; or (c) both the sense strand and the antisense strand each comprise at least one phosphorothioate or methylphosphonate internucleotide linkage.
      • 9. The dsRNA agent of claim 8, wherein the sense strand comprises two phosphorothioate or methylphosphonate internucleotide linkages at the 5′-terminus.
      • 10. The dsRNA agent of claim 8, wherein the antisense strand comprises two phosphorothioate or methylphosphonate internucleotide linkages at each of the 5′-terminus and the 3′-terminus.
      • 11. The dsRNA agent of claim 8, wherein the sense strand comprises two phosphorothioate or methylphosphonate internucleotide linkages at the 5′-terminus and the antisense strand comprises two phosphorothioate or methylphosphonate internucleotide linkages at each of the 5′-terminus and the 3′-terminus.
    • 12. The dsRNA agent of claim 1, wherein at least one strand is conjugated to a ligand.
      • 13. The dsRNA agent of claim 12, wherein the ligand is conjugated to the 3′-end of the sense strand.
    • 14. The dsRNA agent of claim 1, wherein the ligand comprises an N-acetylgalactosamine (GalNAc) derivative.
      • 15. The dsRNA agent of claim 14, wherein the ligand comprises one or more GalNAc derivatives attached through a monovalent linker, a bivalent branched linker, or a trivalent branched linker.
        • 16. The dsRNA agent of claim 15, wherein the ligand comprises:embedded image
          • 17. The dsRNA agent of claim 16, wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic:embedded imageand, wherein X is O.
    • 25. A pharmaceutical composition for inhibiting expression of a gene encoding 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13) comprising the dsRNA agent of claim 1.
      • 26. The pharmaceutical composition of claim 25, wherein the dsRNA agent is in a buffered solution.
        • 27. The pharmaceutical composition of claim 26, wherein the buffered solution comprises acetate, citrate, prolamine, carbonate, phosphate, phosphate buffered saline, or any combination thereof.
  • 18. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13) in a cell, comprising a sense strand and an antisense strand, wherein the nucleotide sequence of the sense strand consists of the nucleotide sequence of SEQ ID NO: 4498 and the nucleotide sequence of the antisense strand consists of the nucleotide sequence of SEQ ID NO: 4499, andwherein at least one of the nucleotides of the sense strand and at least one of nucleotides of the antisense strand comprises a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoro modification.
    • 19. The dsRNA agent of claim 18, wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified.
      • 20. The dsRNA agent of claim 19, wherein the sense strand and the antisense strand each contain at least one 2′-O-methyl modification and at least one 2′-fluoro modification.
        • 21. The dsRNA agent of claim 20, wherein the sense strand and/or the antisense strand each independently contain 1-2 phosphorothioate or methylphosphonate internucleotide linkages at their 5′-termini and/or 3′-termini.
          • 22. The dsRNA agent of claim 21, wherein: (a) the sense strand comprises: (i) four 2′-fluoro modified nucleotides at nucleotides 7 and 9-11, counting from the 5′-end;(ii) seventeen 2′-O-methyl modified nucleotides at nucleotides 1-6, 8, and 12-21, counting from the 5′-end; and(iii) phosphorothioate linkages between nucleotides 1 and 2 and between nucleotides 2 and 3, counting from the 5′-end; and(b) the antisense strand comprises: (i) three 2′-fluoro modified nucleotides at nucleotides 2, 14, and 16, counting from the 5′-end;(ii) nineteen 2′-O-methyl modified nucleotides at nucleotides 1, 3-6, 8-13, 15, and 17-23, counting from the 5′-end;(iii) one glycol modified nucleotide at nucleotide 7, counting from the 5′-end; and(iv) phosphorothioate linkages between nucleotides 1 and 2, between nucleotides 2 and 3, between nucleotides 21 and 22, and between nucleotides 22 and 23, counting from the 5′-end.
            • 23. The dsRNA agent of claim 22, wherein the sense strand is conjugated to a ligand, wherein the ligand comprises a multivalent galactose, an N-acetylgalactosamine, an N-acetylgalactosamine derivative, a divalent N-acetylgalactosamine, or a trivalent N-acetylgalactosamine.
              • 24. The dsRNA agent of claim 23, wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic:embedded imageand, wherein X is O.
                • 28. A pharmaceutical composition for inhibiting expression of a gene encoding 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13) comprising the dsRNA agent of claim 24.
                  • 29. The pharmaceutical composition of claim 28, wherein the dsRNA agent is in a buffered solution.
                    • 30. The pharmaceutical composition of claim 29, wherein the buffered solution comprises acetate, citrate, prolamine, carbonate, phosphate, phosphate buffered saline, or any combination thereof.
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