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

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.