RNAi AGENTS, COMPOSITIONS AND METHODS OF USE THEREOF FOR TREATING TRANSTHYRETIN (TTR) ASSOCIATED DISEASES

Patent metadata

Field	Value
Publication number	US-2024279652-A1
Application number	US-202318509440-A
Country	US
Kind code	A1
Filing date	Nov 15, 2023
Priority date	Nov 18, 2011
Publication date	Aug 22, 2024
Grant date	—

Abstract

The present invention provides RNAi agents, e.g., double stranded RNAi agents, that target the transthyretin (TTR) gene and methods of using such RNAi agents for treating or preventing TTR-associated diseases.

First claim

1 . A double stranded RNAi agent comprising a sense strand complementary to an antisense strand, wherein said antisense strand comprises a region complementary to part of an mRNA encoding transthyretin (TTR), wherein each strand is independently 15 to 30 nucleotides in length, wherein said double stranded RNAi agent is represented by formula (III):

(III)

sense:

5′ n p -N a -(X X X) i -N b -Y Y Y-N b -(Z Z Z) j -N a -n q  3′

antisense:

3′ n p ′-N a ′-(X′X′X′) k -N b ′-Y′Y′Y′-N b ′-(Z′Z′Z′) l -N a ′-

n q ′ 5′

wherein:
i, j, k, and l are each independently 0 or 1;
p, p′, q, and q′ are each independently 0-6;
each N a and N a ′ independently represents an oligonucleotide sequence comprising 0-25 nucleotides which are either modified or unmodified or combinations thereof, each sequence comprising at least two differently modified nucleotides;
each N b and N b ′ independently represents an oligonucleotide sequence comprising 0-10 nucleotides which are either modified or unmodified or combinations thereof,
each n p , n p ′, n q , and n q ′ independently represents an overhang nucleotide;
XXX, YYY, ZZZ, X′X′X′, Y′Y′Y′, and Z′Z′Z′ each independently represent one motif of three identical modifications on three consecutive nucleotides;
modifications on N b differ from the modification on Y and modifications on N b ′ differ from the modification on Y′; and
wherein the sense strand is conjugated to at least one ligand.

2 . The RNAi agent of claim 1 , wherein i is 1; j is 1; or both i and j are 1; or wherein k is 1; l is 1; or both k and l are 1.

3 . (canceled)

4 . The RNAi agent of claim 1 , wherein XXX is complementary to X′X′X′, YYY is complementary to Y′Y′Y′, and ZZZ is complementary to Z′Z′Z′.

5 .- 10 . (canceled)

11 . The RNAi agent of claim 1 , wherein the duplex region is 15-30 nucleotide pairs in length: 17-23 nucleotide pairs in length: 17-25 nucleotide pairs in length: 23-27 nucleotide pairs in length: 19-21 nucleotide pairs in length: or 21-23 nucleotide pairs in length.

12 .- 17 . (canceled)

18 . The RNAi agent of claim 1 , wherein the modifications on the nucleotides are selected from the group consisting of LNA, HNA, CeNA, 2′-methoxyethyl, 2′-O-alkyl, 2′-O-allyl, 2′-C-allyl, 2′-fluoro, 2′-deoxy, 2′-hydroxyl, and combinations thereof.

19 . The RNAi agent of claim 18 , wherein the modifications on the nucleotides are 2′-O-methyl, 2′-fluoro or both.

20 . The RNAi agent of claim 1 , wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.

21 . The RNAi agent of claim 1 , wherein the ligand is

and wherein the ligand is attached to the 3′ end of the sense strand.

22 . (canceled)

23 . The RNAi agent of claim 21 , wherein the RNAi agent is conjugated to the ligand as shown in the following schematic

wherein X is O or S.

24 .- 41 . (canceled)

42 . A pharmaceutical composition comprising the RNAi agent of claim 1 .

43 .- 49 . (canceled)

50 . A method of inhibiting expression of a transthyretin (TTR) in a cell comprising contacting said cell with the RNAi agent of claim 1 in an amount effective to inhibit expression of said TTR in said cell, thereby inhibiting expression of said transthyretin (TTR) in said cell.

51 . (canceled)

52 . (canceled)

53 . The method of claim 50 , wherein said cell is present within a subject.

54 . The method of claim 53 , wherein said subject is a human.

55 .- 78 . (canceled)

79 . A method of treating or preventing a TTR-associated disease in a subject, comprising administering to said subject a therapeutically effective amount or a prophylactically effective amount of the RNAi agent of claim 1 , thereby treating or preventing said TTR-associated disease in said subject.

80 . (canceled)

81 . The method of claim 79 , wherein said subject is a human.

82 . The method of claim 79 , wherein said subject is a subject suffering from a TTR-associated disease.

83 . (canceled)

84 . The method of claim 79 , wherein said subject carries a TTR gene mutation that is associated with the development of a TTR-associated disease.

85 . The method of claim 79 , wherein said TTR-associated disease is selected from the group consisting of senile systemic amyloidosis (SSA), systemic familial amyloidosis, familial amyloidotic polyneuropathy (FAP), familial amyloidotic cardiomyopathy (FAC), leptomeningeal/Central Nervous System (CNS) amyloidosis, and hyperthyroxinemia.

86 . (canceled)

87 . (canceled)

88 . The method of claim 79 , wherein said RNAi agent is administered to said subject via subcutaneous, intramuscular or intravenous administration.

89 .- 96 . (canceled)

97 . The method of claim 79 , further comprising assessing the level of TTR mRNA expression or TTR protein expression in a sample derived from the subject.

98 .- 113 . (canceled)

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Rajeev Kallanthottathil G
• Zimmermann Tracy
• Manoharan Muthiah
• Maier Martin A
• Kuchimanchi Satyanarayana
• Charisse Klaus

Classifications

• C12N2320/30

  Special therapeutic applications · CPC title

• C12N2310/322

  2'-R Modification · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title

• C12N15/1136

  against growth factors, growth regulators, cytokines, lymphokines or hormones · CPC title

• C12N2310/351

  Conjugate · CPC title