TMPRSS6 iRNA compositions and methods of use thereof
View Patent ↗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.
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.