Angiopoietin-like 3 (ANGPTL3) iRNA compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12492401-B2
Application number	US-202318337495-A
Country	US
Kind code	B2
Filing date	Jun 20, 2023
Priority date	Apr 13, 2015
Publication date	Dec 9, 2025
Grant date	Dec 9, 2025

Abstract

The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the ANGPTL3 gene, as well as methods of inhibiting expression of ANGPTL3 and methods of treating subjects having a disorder of lipid metabolism, such as hyperlipidemia or hypertriglyceridemia, using such dsRNA compositions.

First claim

We claim:

1 . A double stranded ribonucleic acid (dsRNA) for inhibiting expression of angiopoietin-like 3 (ANGPTL3), or a salt thereof,
wherein said dsRNA, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises at least 19 contiguous nucleotides from the nucleotide sequence 5′-CUCCATAGAGAAGCAATCUAA-3′ of SEQ ID NO:373 and the antisense strand comprising at least 19 contiguous nucleotides from the nucleotide sequence 5′-UTAGAUUGCUUCACUAUGGAGUA-3′ of SEQ ID NO:394.

2 . The dsRNA, or a salt thereof, of claim 1 , wherein at least one nucleotide of the dsRNA comprises a nucleotide modification.

3 . The dsRNA, or a salt thereof, of claim 1 , further comprising at least one phosphorothioate internucleotide linkage.

4 . The dsRNA, or a salt thereof, of claim 3 , comprising 6-8 phosphorothioate internucleotide linkages.

5 . The dsRNA, or a salt thereof, of claim 1 , wherein the sense strand and the antisense strand are each, independently, 19-23 nucleotides in length; or 19 nucleotides in length.

6 . The dsRNA, or a salt thereof, of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide; or at least 2 nucleotides.

7 . The dsRNA, or a salt thereof, of claim 1 , further comprising a ligand.

8 . The dsRNA, or a salt thereof, of claim 7 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA.

9 . The dsRNA, or a salt thereof, of claim 8 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

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

11 . The dsRNA, or a salt thereof, of claim 7 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, a bivalent, or a trivalent branched linker.

12 . The dsRNA, or a salt thereof, of claim 1 , wherein the double stranded region is 19-25 nucleotide pairs in length; 19-21 nucleotide pairs in length; or 21-23 nucleotide pairs in length.

13 . The dsRNA, or a salt thereof, of claim 1 , wherein each strand is independently 19-25 nucleotides in length; or each strand is independently 21-23 nucleotides in length.

14 . The dsRNA, or a salt thereof, of claim 1 , wherein the antisense strand comprises the nucleotide sequence 5′-UTAGAUUGCUUCACUAUGGAGUA-3′ of SEQ ID NO: 394.

15 . The dsRNA, or a salt thereof, of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-CUCCATAGAGAAGCAATCUAA-3′ of SEQ ID NO: 373 and the antisense strand comprises the nucleotide sequence 5′-UTAGAUUGCUUCACUAUGGAGUA-3′ of SEQ ID NO:394.

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

17 . A pharmaceutical composition for inhibiting expression of an ANGPTL3 gene comprising the dsRNA, or a salt thereof, of claim 1 .

18 . A method of inhibiting ANGPTL3 expression in a cell, the method comprising:
(a) contacting the cell with the dsRNA, or a 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 an ANGPTL3 gene, thereby inhibiting expression of the ANGPTL3 gene in the cell.

19 . The method of claim 18 , wherein said cell is within a subject.

20 . The method of claim 19 , wherein the subject is a human.

21 . The method of claim 20 , wherein the human subject suffers from a disorder of lipid metabolism.

22 . A method of treating a subject having a disorder that would benefit from a reduction in ANGPTL3 expression, comprising administering to the subject a therapeutically effective amount of the dsRNA, or a salt thereof, of claim 1 , thereby treating said subject.

23 . A double stranded ribonucleic acid (dsRNA) for inhibiting expression of angiopoietin-like 3 (ANGPTL3), or a salt thereof, comprising a sense strand and an antisense strand forming a double stranded region,
wherein the sense comprises at least 19 contiguous nucleotides from the nucleotide sequence 5′-CUCCATAGAGAAGCAATCUAA-3′ of SEQ ID NO:373 and the antisense strand comprises at least 19 contiguous nucleotides from the nucleotide sequence 5′-UTAGAUUGCUUCACUAUGGAGUA-3′ of SEQ ID NO:394, wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification selected from the group consisting of a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, a deoxy-nucleotide modification, a thymidine-glycol nucleic acid (GNA) S-Isomer modification, a nucleotide comprising a 5′-phosphorothioate group modification, an abasic nucleotide modification, and a 2′-amino nucleotide modification, and wherein a ligand comprising N-acetylgalactosamine (GalNAc) is conjugated to at least one strand.

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Querbes William
• Fitzgerald Kevin
• Butler James
• Williams Stephanie
• Hinkle Gregory
• Maier Martin A

Classifications

• C12N2320/35

  based on a specific dosage / administration regimen · CPC title

• C12N2320/32

  Special delivery means, e.g. tissue-specific · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• A61K47/549

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title

• C12N2310/3515

  Lipophilic moiety, e.g. cholesterol · CPC title