TMPRSS6 iRNA compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10246713-B2
Application number	US-201715603560-A
Country	US
Kind code	B2
Filing date	May 24, 2017
Priority date	Nov 24, 2014
Publication date	Apr 2, 2019
Grant date	Apr 2, 2019

Abstract

The invention relates to RNAi agents, e.g., double-stranded RNAi agents, targeting the TMPRSS6 gene, and methods of using such RNAi agents to inhibit expression of TMPRSS6 and methods of treating subjects having a TMPRSS6 associated disorder, e.g., an iron overload associated disorder, such as β-thalassemia or hemochromatosis.

First claim

We claim:

1. A double stranded RNAi agent for inhibiting expression of TMPRSS6 in a cell, wherein said double stranded RNAi agent comprises a sense strand and an antisense strand forming a duplex, wherein the sense strand comprises any one of the modified nucleotide sequences selected from the group consisting of SEQ ID NOS: 62-86, 112-127, and 144-147, and the antisense strand comprises any one of the modified nucleotide sequences selected from the group consisting of SEQ ID NOS: 87-111, 128-143, and 148-151, and wherein the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length.

2. The double stranded RNAi agent of claim 1 , wherein the sense strand and the antisense strand comprise the sense and antisense strand nucleotide sequences of a duplex selected from the group consisting of AD-63202, AD-64372, AD-64373, AD-64374, AD-64375, AD-64376, AD-64377, AD-64378, AD-64380, AD-64381, AD-64382, AD-64384, AD-64385, AD-64386, AD-64387, AD-64389, AD-64601, AD-64569, AD-64604, AD-64567, AD-60940, AD-65105, AD-65106, AD-65107, AD-65108, AD-65109, AD-65110, AD-65111, AD-65112, AD-61002, AD-66014, AD-66015, and AD-65189.

3. The double stranded RNAi agent of claim 1 , further comprising a ligand.

4. The double stranded RNAi agent of claim 3 , wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.

5. The double stranded RNAi agent of claim 3 , wherein the ligand is

6. The double stranded RNAi agent of claim 3 , wherein the ligand is attached to the 3′ end of the sense strand.

7. The double stranded RNAi agent of claim 6 , wherein the RNAi agent is conjugated to the ligand as shown in the following schematic

wherein X is O or S.

8. A pharmaceutical composition comprising the double stranded RNAi agent of claim 1 .

9. The double stranded RNAi agent of claim 1 , wherein
the sense strand comprises the nucleotide sequence 5′-csusggudAuuucdCuaggg(Tgn)acaa-3′ (SEQ ID NO: 120) and the antisense strand comprises the nucleotide sequence 5′-usUsguacccudAggadAauaccagsasg-3′ (SEQ ID NO: 136),
wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U; U is uridine-3′-phosphate; s is a phosphorothioate linkage; dA is 2′-deoxyadenosine; dC is 2′-deoxycytosine; and (Tgn) is thymidine-glycol nucleic acid (GNA)S-Isomer.

10. The double stranded RNAi agent of claim 9 , further comprising a ligand.

11. The double stranded RNAi agent of claim 10 , wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.

12. The double stranded RNAi agent of claim 10 , wherein the ligand is

13. The double stranded RNAi agent of claim 10 , wherein the ligand is attached to the 3′ end of the sense strand.

14. The double stranded RNAi agent of claim 13 , wherein the RNAi agent is conjugated to the ligand as shown in the following schematic

wherein X is O or S.

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Butler James
• Maier Martin
• Fitzgerald Kevin
• Fishman Shannon
• Foster Donald
• Jadhav Vasant
• Milstein Stuart

Classifications

• A61P7/06

  Antianaemics · CPC title

• C12Y304/21

  Serine endopeptidases (3.4.21) · CPC title

• C12N2320/31

  Combination therapy · CPC title

• C12N15/1138

  against receptors or cell surface proteins · CPC title

• C12N2310/3533

  Halogen · CPC title