Factor XII (hageman factor) (F12), kallikrein B, plasma (fletcher factor) 1 (KLKB1), and kininogen 1 (KNG1) iRNA compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12338439-B2
Application number	US-202318218155-A
Country	US
Kind code	B2
Filing date	Jul 5, 2023
Priority date	May 6, 2015
Publication date	Jun 24, 2025
Grant date	Jun 24, 2025

Abstract

The present invention relates to RNAi agents, e.g., double stranded RNAi agents, targeting the Kallikrein B, Plasma (Fletcher Factor) 1 (KLKB1) gene, the Factor XII (Hageman Factor (F12) gene, or the Kininogen 1 (KNG1) gene, and methods of using such RNAi agents to inhibit expression of a KLKB1 gene, an F12 gene, and/or a KNG1 gene, and methods of treating subjects having an hereditary angioedema (HAE) and/or a contact activation pathway-associated disorder.

First claim

We claim:

1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Factor XII (Hageman Factor) (F12), 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 sense strand comprises at least 19 contiguous nucleotides from nucleotides 433-460 of the nucleotide sequence of SEQ ID NO:9 and the antisense strand comprises at least 19 contiguous nucleotides from the corresponding nucleotides of the nucleotide sequence of SEQ ID NO:10,
wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification, and
wherein the sense strand is conjugated to a ligand attached at the 3′-terminus.

2. The dsRNA agent, or a salt thereof, of claim 1 , wherein the at least one 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, 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, and a nucleotide comprising a 5′-phosphate mimic modification.

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

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; or a 3′ overhang of at least 2 nucleotides.

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

7. The dsRNA agent, or a salt thereof, of claim 6 , wherein the ligand is

8. The dsRNA agent, or a salt thereof, of claim 7 , wherein the dsRNA agent, or a salt thereof, is conjugated to the ligand as shown in the following schematic

and, wherein X is O or S.

9. The dsRNA agent, or a salt thereof, of claim 1 , wherein the sense strand and the antisense strand comprise nucleotide sequences selected from the group consisting of:

(SEQ ID NO: 402)

(a) 5′-CUGCCAGAAAGAGAAGUGCUU-3′

and 

(SEQ ID NO: 452)

5′-AAGCACUUCUCUUUCUGGCAGUG-3′; 

and

(SEQ ID NO: 403)

(b) 5′-CAGAAAGAGAAGUGCUUUGAA-3′

and

(SEQ ID NO: 453)

5′-UUCAAAGCACUUCUCUUUCUGGC-3′.

10. The dsRNA agent, or a salt thereof, of claim 1 , further comprising 6-8 phosphorothioate internucleotide linkages.

11. A cell containing the dsRNA agent, or a salt thereof, of claim 1 .

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

13. A method of inhibiting expression of a contact activation pathway gene in a cell, the method comprising:
(a) contacting the cell with the dsRNA agent, 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 the contact activation pathway gene, thereby inhibiting expression of the contact activation pathway gene in the cell.

14. A method of treating a subject having a disease or disorder that would benefit from reduction in expression of a contact activation pathway gene, the method comprising administering to the subject a therapeutically effective amount of the dsRNA agent, or a salt thereof, of claim 1 , thereby treating said subject.

15. The method of claim 14 , wherein the disorder is a contact activation pathway-associated disease.

16. The method of claim 14 , wherein the subject is human.

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Akinc Akin
• Hinkle Gregory
• Maier Martin A
• Butler James
• Liu Jingxuan

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C12N2310/344

  Position-specific modifications, e.g. on every purine, at the 3'-end · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title

• C12N2310/322

  2'-R Modification · CPC title