TMPRSS6 iRNA compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11725209-B2
Application number	US-202017062748-A
Country	US
Kind code	B2
Filing date	Oct 5, 2020
Priority date	Nov 24, 2014
Publication date	Aug 15, 2023
Grant date	Aug 15, 2023

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 comprising any one of the modified nucleotide sequences selected from the group consisting of SEQ ID NOS: 62-86, 112-127, and 144-147, and an antisense strand comprising 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-64601, 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. A method of inhibiting TMPRSS6 expression in a cell, the method comprising:
(a) contacting the cell with the double stranded RNAi agent of claim 1 or the pharmaceutical composition of claim 8 ; and
(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a TMPRSS6 gene, thereby inhibiting expression of the TMPRSS6 gene in the cell.

10. The method of claim 9 , wherein said cell is within a subject.

11. The method of claim 10 , wherein the subject is a human.

12. The method of claim 9 , wherein TMPRSS6 expression is inhibited by at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98% or about 100%.

13. The method of claim 10 , wherein serum hepcidin concentration in said subject is increased by at least about 10%; and/or wherein serum iron concentration in said subject is decreased by at least about 20%; and/or wherein a percent transferrin saturation in said subject is decreased by at least about 20%.

14. A method of treating a subject having a TMPRSS6 associated disorder, comprising administering to the subject a therapeutically effective amount of the double stranded RNAi agent of claim 1 , or the pharmaceutical composition of claim 8 , thereby treating the subject.

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

16. The method of claim 15 , wherein the human has hereditary hemochromatosis, β-thalassemia, or erythropoietic porphyria.

17. The method of claim 15 , wherein the human has a disorder associated with iron overload.

18. The method of claim 14 , wherein the double stranded RNAi agent is administered to the subject subcutaneously; or intravenously.

19. The method of claim 14 , further comprising administering an iron chelator to the subject.

20. The double stranded RNAi agent of claim 1 ,
wherein the sense strand comprises the nucleotide sequence 5′-csusgguaUfuUfCfCfuaggGfdTacaa-3′ (SEQ ID NO: 72) and the antisense strand comprises the nucleotide sequence 5′- usUfsguaCfccuaggaAfaUfaccagsasg-3′ (SEQ ID NO: 97),
wherein a, c, g, and u are 2′-O-methyladenosine-3′-phosphate, 2′-O-methylcytidine-3′-phosphate, 2′-O-methylguanosine-3′-phosphate, and 2′-O-methyluridine-3′-phosphate, respectively; Af, Cf, Gf, and Uf are 2′-fluoroadenosine-3′-phosphate, 2′-fluorocytidine-3′-phosphate, 2′-fluoroguanosine-3′-phosphate, and 2′-fluorouridine-3′-phosphate, respectively; s is a phosphorothioate linkage; and dT is 2′-deoxythymidine.

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

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

Classifications

• C12N15/1137 Primary

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

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C12N15/1138

  against receptors or cell surface proteins · CPC title

• C12Y304/21

  Serine endopeptidases (3.4.21) · CPC title