Polynucleotide agents targeting factor XII (hageman factor) (F12) and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10883107-B2
Application number	US-201716068444-A
Country	US
Kind code	B2
Filing date	Jan 6, 2017
Priority date	Jan 8, 2016
Publication date	Jan 5, 2021
Grant date	Jan 5, 2021

Abstract

The invention relates to polynucleotide agents targeting Factor XII (F12) gene, and methods of using such polynucleotide agents to inhibit expression of Factor XII and to treat subjects having a Factor XII-associated disease, e.g., heredity angioedema (HAE), prekallikrein deficiency, malignant essential hypertension, hypertension, end stage renal disease, or Fletcher Factor Deficiency.

First claim

I claim:

1. A single stranded antisense polynucleotide agent for inhibiting expression of a Factor XII (F12) gene, wherein the agent comprises 14 to 20 contiguous nucleotides, wherein at least one of the contiguous nucleotides is a modified nucleotide, and wherein the nucleotide sequence of the agent is fully complementary over its entire length to nucleotides 287-306 of SEQ ID NO:1.

2. The agent of claim 1 , wherein substantially all of the nucleotides of the antisense polynucleotide agent are modified nucleotides.

3. The agent of claim 1 , wherein all of the nucleotides of the antisense polynucleotide agent are modified nucleotides.

4. The agent of claim 1 , which is 14 nucleotides in length or 20 nucleotides in length.

5. The agent of claim 1 , wherein the modified nucleotide comprises a modified sugar moiety selected from the group consisting of: a 2′-O-methoxyethyl modified sugar moiety, a 2′-methoxy modified sugar moiety, a 2′-O-alkyl modified sugar moiety, a bicyclic sugar moiety, a 5-methylcytosine, and a modified internucleoside linkage.

6. The agent of claim 5 , wherein the bicyclic sugar moiety has a (—CRH—)n group forming a bridge between the 2′ oxygen and the 4′ carbon atoms of the sugar ring, wherein n is 1 or 2 and wherein R is H, CH 3 or CH 3 OCH 3 .

7. The agent of claim 5 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

8. The agent of claim 1 , wherein the agent is a gapmer comprising a plurality of 2′-deoxynucleotides flanked on each of a 5′ and a 3′ side by a wing segment comprising at least one nucleotide having a modified sugar moiety.

9. The agent of claim 8 , wherein the modified sugar moiety is selected from the group consisting of a 2′-O-methoxyethyl modified sugar moiety, a 2′-methoxy modified sugar moiety, a 2′-O-alkyl modified sugar moiety, and a bicyclic sugar moiety.

10. The agent of claim 8 , wherein the 5′-wing segment is 1 to 6 nucleotides in length; 2 nucleotides in length; 3 nucleotides in length; 4 nucleotides in length; or 5 nucleotides in length.

11. The agent of claim 8 , wherein the 3′-wing segment is 1 to 6 nucleotides in length; 2 nucleotides in length; 3 nucleotides in length; 4 nucleotides in length; or 5 nucleotides in length.

12. The agent of claim 8 , wherein the gap segment is 5 to 14 nucleotides in length; or 10 nucleotides in length.

13. The agent of claim 1 , wherein the agent further comprises a ligand.

14. The agent of claim 13 , wherein the antisense polynucleotide agent is conjugated to the ligand at the 3′-terminus.

15. The agent of claim 13 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

16. The agent of claim 15 , wherein the ligand is

17. A pharmaceutical composition for inhibiting expression of a Factor XII gene, comprising the agent of claim 1 .

18. A method of inhibiting expression of a Factor XII (F12) gene in a cell, the method comprising:
(a) contacting the cell with the agent of claim 1 ; and
(b) maintaining the cell produced in step (a) for a time sufficient to obtain antisense inhibition of a Factor XII (F12) gene, thereby inhibiting expression of the Factor XII gene in the cell.

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Hinkle Gregory

Classifications

• C12N15/113 Primary

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• C12N2310/351

  Conjugate · CPC title

• A61K31/585

  containing lactone rings, e.g. oxandrolone, bufalin · CPC title

• C12N15/1137 Primary

  against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138) · CPC title

• C12N2310/11

  Antisense · CPC title