Granted Patent B2

US 12,416,006 · App. 18/928,880 · Granted Sep 16, 2025

Inventors: Jeffrey Zuber (Somerville, MA); James D. McIninch (Burlington, MA); Mark K. Schlegel (Lexington, MA); Adam Castoreno (Framingham, MA); Lucas Bondurant (Brookline, MA); Dhaval Oza (Boston, MA)

Assignee: Alnylam Pharmaceuticals, Inc.

C12N15/113A61K31/713C12N2310/14C12N2310/3125C12N2310/315C12N2310/321C12N2310/322C12N2310/351

Abstract

Claims (67)

1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of cell death-inducing DFFA-like effector b (CIDEB) in a cell, or a salt thereof,

wherein said dsRNA agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region,

wherein the sense strand consists of the nucleotide sequence

(SEQ ID NO: 705)

5′-AGUAUCUAAUAUAAGCUCGGU-3′ of

and the antisense strand consists of the nucleotide sequence

(SEQ ID NO: 1153)

5′-ACCGAGCUUAUAUUAGAUACUGA-3′ of

wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification;

wherein a ligand is conjugated to the 3′ end of the sense strand; and

wherein the ligand is

2. The dsRNA agent, or a salt thereof, of claim 1 , wherein the dsRNA agent, or a salt thereof, is conjugated to the ligand as shown in the following schematic

wherein X is O or S.

3. The dsRNA agent, or a salt thereof, of claim 2 , wherein X is O.

4. The dsRNA agent, or a salt thereof, of claim 1 , wherein the dsRNA agent, or a salt thereof, further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.

5. The dsRNA agent, or a salt thereof, of claim 4 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 3′-terminus of the sense strand or the antisense strand.

6. The dsRNA agent, or a salt thereof, of claim 4 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 5′-terminus of the sense strand or the antisense strand.

7. The dsRNA agent, or a salt thereof, of claim 4 , wherein the dsRNA agent comprises 6-8 phosphorothioate internucleotide linkages.

8. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of cell death-inducing DFFA-like effector b (CIDEB) in a cell, or a salt thereof, comprising a sense strand and an antisense strand forming a double stranded region,

wherein the antisense strand comprises the nucleotide sequence 5′-asdCscgdAgdCuuaudAuUfagauacusgsa-3′ of SEQ ID. NO: 2049,

wherein

s is a phosphorothioate linkage;

a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively;

dA is 2′-deoxyadenosine-3′-phosphate;

dC is 2′-deoxycytidine-3′-phosphate; and

Uf is 2′-fluoro U.

9. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of cell death-inducing DFFA-like effector b (CIDEB) in a cell, or a salt thereof, comprising a sense strand and an antisense strand forming a double stranded region,

wherein the sense strand consists of the nucleotide sequence, 5′-asgsuaucuaAfUfAfuaagcucggu-3′ of SEQ ID. NO: 1601 and the antisense strand consists of the nucleotide sequence 5′-asdCscgdAgdCuuaudAuUfagauacusgsa-3′ of SEQ ID. NO: 2049,

wherein

s is a phosphorothioate linkage;

a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively;

dA is 2′-deoxyadenosine-3′-phosphate;

dC is 2′-deoxycytidine-3′-phosphate; and

Af and Uf are 2′-fluoro A and U, respectively, and

wherein the 3′-end of the sense strand is conjugated to a ligand as shown in the following schematic

wherein X is O.

10. The dsRNA agent of claim 9 which is in sodium salt form.

11. A pharmaceutical composition for inhibiting expression of cell death-inducing DFFA-like effector b (CIDEB) gene, comprising the dsRNA agent, or a salt thereof, of claim 9 .

12. The pharmaceutical composition of claim 11 , wherein the dsRNA agent, or a salt thereof, is present in an unbuffered solution.

13. The pharmaceutical composition of claim 11 , wherein the dsRNA agent, or a salt thereof, is present in saline or water.

14. The pharmaceutical composition of claim 11 , wherein the dsRNA agent, or a salt thereof, is present in a buffer solution.

15. The pharmaceutical composition of claim 14 , wherein the buffer solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof.

16. The pharmaceutical composition of claim 14 , wherein the buffer solution is phosphate buffered saline (PBS).

17. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of cell death-inducing DFFA-like effector b (CIDEB) in a cell, or a salt thereof, comprising a sense strand and an antisense strand forming a double stranded region,

wherein the sense strand comprises the nucleotide sequence 5′-asgsuaucuaAfUfAfuaagcucggu-3′ of SEQ ID. NO: 1601 and the antisense strand comprises the nucleotide sequence 5′-asdCscgdAgdCuuaudAuUfagauacusgsa-3′ of SEQ ID. NO: 2049,

wherein

s is a phosphorothioate linkage;

a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively;

dA is 2′-deoxyadenosine-3′-phosphate;

dC is 2′-deoxycytidine-3′-phosphate; and

Af and Uf are 2′-fluoro A and U, respectively.

18. The dsRNA agent, or a salt thereof, of claim 17 , further comprising a ligand.

19. The dsRNA agent, or a salt thereof, of claim 18 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent, or a salt thereof.

20. The dsRNA agent, or a salt thereof, of claim 18 , wherein the ligand comprises N-acetylgalactosamine (GalNAc).

21. The dsRNA agent, or a salt thereof, of claim 20 , wherein the ligand is

22. The dsRNA agent, or a salt thereof, of claim 21 , wherein the dsRNA agent, or a salt thereof, is conjugated to the ligand as shown in the following schematic

wherein X is O or S.

23. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of cell death-inducing DFFA-like effector b (CIDEB) in a cell, or a salt thereof, comprising a sense strand and an antisense strand forming a double stranded region,

wherein the sense strand comprises the nucleotide sequence 5′-asgsuaucuaAfUfAfuaagcucggu-3′ of SEQ ID. NO: 1601 and the antisense strand comprises the nucleotide sequence 5′-asdCscgdAgdCuuaudAuUfagauacusgsa-3′ of SEQ ID. NO: 2049,

wherein

s is a phosphorothioate linkage;

a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively;

dA is 2′-deoxyadenosine-3′-phosphate;

dC is 2′-deoxycytidine-3′-phosphate; and

Af and Uf are 2′-fluoro A and U, respectively, and

wherein the 3′-end of the sense strand is conjugated to a ligand as shown in the following schematic

wherein X is O.

Assignments (2)

Continuity (4)

References Cited (400)