Granted Patent B2

US 12,559,755 · App. 18/374,166 · Granted Feb 24, 2026

Inventors: David Bumcrot (Cambridge, MA); Brian Bettencourt (Groton, MA); Ivanka Toudjarska (Medford, MA)

Assignee: Alnylam Pharmaceuticals, Inc.

C12N15/1138A61K31/713C12N15/1137C12Y304/21C12N2310/14C12N2310/315C12N2310/321C12N2310/344C12N2310/346C12N2310/351C12N2320/30

Abstract

Claims (19)

1 . A double-stranded ribonucleic acid (dsRNA), or a pharmaceutically acceptable salt thereof, for inhibiting expression of TMPRSS6 in a cell, comprising a sense strand and an antisense strand forming a double-stranded region,

wherein the antisense strand comprises at least 16 contiguous nucleotides which differ by no more than 3 nucleotides from the nucleotide sequence AGAAUGAACCAGAAGAAGC (SEQ ID NO:110),

wherein each strand is independently 16 to 30 nucleotides in length,

wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides, and

wherein the 3′ end of the sense strand is conjugated to a ligand comprising an N-acetylgalactosamine (GalNAc) derivative.

2 . The dsRNA, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein at least one of said modified nucleotides is selected from the group consisting of a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group, a locked nucleotide, an abasic nucleotide, a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide.

3 . The dsRNA, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein said modified nucleotide is selected from the group consisting of a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, a 2′-deoxy-2′-fluoro modified nucleotide, and a 2′-deoxy-modified nucleotide.

4 . The dsRNA, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein each strand is independently 19 to 24 nucleotides in length.

5 . The dsRNA, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein each strand is independently 19 to 21 nucleotides in length.

6 . The dsRNA, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein each strand is no more than 30 nucleotides in length.

7 . The dsRNA, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein at least one strand comprises an overhang of at least 1 nucleotide or at least 2 nucleotides.

8 . An isolated cell containing the dsRNA, or a pharmaceutically acceptable salt thereof, of claim 1 .

9 . A pharmaceutical composition for inhibiting expression of a TMPRSS6 gene comprising the dsRNA, or a pharmaceutically acceptable salt thereof, of claim 1 .

10 . A method of inhibiting TMPRSS6 expression in a cell, the method comprising:

(a) introducing into the cell the dsRNA, or a pharmaceutically acceptable salt thereof, of claim 1 ; and

(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a TMPRSS6 gene, thereby inhibiting expression of the TMPRSS6 gene in the cell.

11 . A method of treating a disorder mediated by TMPRSS6 expression comprising administering to a human in need of such treatment a therapeutically effective amount of the dsRNA, or a pharmaceutically acceptable salt thereof, of claim 1 .

12 . The dsRNA, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the dsRNA, or a pharmaceutically acceptable salt thereof, further comprises at least one phosphorothioate internucleotide linkage.

13 . The dsRNA, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the ligand comprises the structure:

Assignments (3)

Continuity (7)

References Cited (104)