Granted Patent B2

US 12,486,512 · App. 17/768,914 · Granted Dec 2, 2025

Inventors: Lucas D. Ward (Cambridge, MA); Ho-Chou Tu (Cambridge, MA); James D. McIninch (Cambridge, MA); Paul Nioi (Cambridge, MA)

Assignee: Alnylam Pharmaceuticals, Inc.

C12N15/1138C12N2310/14C12N2310/351

Abstract

Claims (32)

1 . A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of solute carrier family 39 member 8 (SLC39A8) in a cell, or a salt thereof,

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

wherein the antisense strand comprises at least 19 contiguous nucleotides from any one of the antisense strand nucleotide sequences selected from the group consisting of

5′-UGAGAAACCAUGAAGAGAAAAGA-3′ of SEQ ID NO: 1465;

5′-UAACCAUGAAGAGAAAAGAUGUC-3′ of SEQ ID NO:1468;

5′-UCAUGAAGAGAAAAGAUGUCUUC-3′ of SEQ ID NO:1471;

5′-UCCAUGAAGAGAAAAGAUGUCUU-3′ of SEQ ID NO:1470;

5′-UGAAACCAUGAAGAGAAAAGAUG-3′ of SEQ ID NO:1476; and

5′-UACCAUGAAGAGAAAAGAUGUCU-3′ of SEQ ID NO:1477,

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

wherein at least one strand is conjugated to a ligand.

2 . The dsRNA agent, or a salt thereof, of claim 1 , wherein at least one of the nucleotide modifications is selected from the group consisting of a deoxy-nucleotide modification, a 3′-terminal deoxy-thymine (dT) nucleotide modification, a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, a 2′-deoxy-nucleotide modification, a locked nucleotide modification, an unlocked nucleotide modification, a conformationally restricted nucleotide modification, a constrained ethyl nucleotide modification, an abasic nucleotide modification, a 2′-amino-nucleotide modification, a 2′-O-allyl-nucleotide modification, 2′-C-alkyl-nucleotide modification, 2′-hydroxly-nucleotide modification, a 2′-methoxyethyl nucleotide modification, a 2′-O-alkyl-nucleotide modification, a morpholino nucleotide modification, a phosphoramidate modification, a non-natural base comprising nucleotide modification, a tetrahydropyran nucleotide modification, a 1,5-anhydrohexitol nucleotide modification, a cyclohexenyl nucleotide modification, a nucleotide comprising a phosphorothioate group modification, a nucleotide comprising a methylphosphonate group modification, a nucleotide comprising a 5′-phosphate modification, a nucleotide comprising a 5′-phosphate mimic modification, a thermally destabilizing nucleotide modification, a glycol nucleotide (GNA) modification, and a 2-O—(N-methylacetamide) nucleotide modification; and combinations thereof.

3 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the double stranded region is 19-25 nucleotide pairs in length.

4 . The dsRNA agent, or a salt thereof, of claim 1 , wherein each strand is independently 19-25 nucleotides in length.

5 . The dsRNA agent, or a salt thereof, of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide.

6 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent, or a salt thereof.

7 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

8 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker.

9 . The dsRNA agent, or a salt thereof, of claim 7 , wherein the ligand is

10 . The dsRNA agent, or a salt thereof, of claim 9 , 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.

11 . The dsRNA agent, or a salt thereof, of claim 10 , wherein X is O.

12 . 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.

13 . An isolated cell containing the dsRNA agent, or a salt thereof, of claim 1 .

14 . A pharmaceutical composition comprising the dsRNA agent, or a salt thereof, of claim 1 .

15 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the antisense strand comprises the nucleotide sequence 5′-UGAGAAACCAUGAAGAGAAAAGA-3′ of SEQ ID NO:1465.

16 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-UUUUCUCUUCAUGGUUUCUCA-3′ of SEQ ID NO:1375 and the antisense strand comprises the nucleotide sequence 5′-UGAGAAACCAUGAAGAGAAAAGA-3′ of SEQ ID NO:1465.

17 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-CAUCUUUUCUCUUCAUGGUUA-3′ of SEQ ID NO:1378 and the antisense strand comprises the nucleotide sequence 5′-UAACCAUGAAGAGAAAAGAUGUC-3′ of SEQ ID NO:1468.

18 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-AGACAUCUUUUCUCUUCAUGA-3′ of SEQ ID NO:1381 and the antisense strand comprises the nucleotide sequence 5′-UCAUGAAGAGAAAAGAUGUCUUC-3′ of SEQ ID NO:1471.

19 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-GACAUCUUUUCUCUUCAUGGA-3′ of SEQ ID NO:1380 and the antisense strand comprises the nucleotide sequence 5′-UCCAUGAAGAGAAAAGAUGUCUU-3′ of SEQ ID NO:1470.

20 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-UCUUUUCUCUUCAUGGUUUCA-3′ of SEQ ID NO:1386 and the antisense strand comprises the nucleotide sequence 5′-UGAAACCAUGAAGAGAAAAGAUG-3′ of SEQ ID NO:1476.

21 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-ACAUCUUUUCUCUUCAUGGUA-3′ of SEQ ID NO:1387 and the antisense strand comprises the nucleotide sequence 5′-UACCAUGAAGAGAAAAGAUGUCU-3′ of SEQ ID NO:1477.

Assignments (2)

Continuity (3)

References Cited (20)