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NZ739169B2 - TRANSTHYRETIN (TTR) iRNA COMPOSITIONS AND METHODS OF USE THEREOF FOR TREATING OR PREVENTING TTR-ASSOCIATED DISEASES - Google Patents
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NZ739169B2 - TRANSTHYRETIN (TTR) iRNA COMPOSITIONS AND METHODS OF USE THEREOF FOR TREATING OR PREVENTING TTR-ASSOCIATED DISEASES - Google Patents

TRANSTHYRETIN (TTR) iRNA COMPOSITIONS AND METHODS OF USE THEREOF FOR TREATING OR PREVENTING TTR-ASSOCIATED DISEASES

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Publication number
NZ739169B2
NZ739169B2 NZ739169A NZ73916916A NZ739169B2 NZ 739169 B2 NZ739169 B2 NZ 739169B2 NZ 739169 A NZ739169 A NZ 739169A NZ 73916916 A NZ73916916 A NZ 73916916A NZ 739169 B2 NZ739169 B2 NZ 739169B2
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New Zealand
Prior art keywords
salt
rnai agent
double stranded
nucleotide
stranded rnai
Prior art date
Application number
NZ739169A
Other versions
NZ739169A (en
Inventor
Amy Chan
Vasant Jadhav
Martin Maier
Kallanthottathil G Rajeev
Tracy Zimmermann
Original Assignee
Alnylam Pharmaceuticals Inc
Filing date
Publication date
Application filed by Alnylam Pharmaceuticals Inc filed Critical Alnylam Pharmaceuticals Inc
Priority to NZ778442A priority Critical patent/NZ778442B2/en
Priority claimed from PCT/US2016/044359 external-priority patent/WO2017023660A1/en
Publication of NZ739169A publication Critical patent/NZ739169A/en
Publication of NZ739169B2 publication Critical patent/NZ739169B2/en

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Abstract

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

Claims (41)

We claim:
1. A double stranded ribonucleic acid (RNAi) agent, or a salt thereof, for inhibiting expression of transthyretin (TTR) in a cell, wherein the RNAi agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises the nucleotide sequence 5’- UGGGAUUUCAUGUAACCAAGA -3’ of SEQ ID NO:2 and the antisense strand comprises the nucleotide sequence 5’- UCUUGGUUACAUGAAAUCCCAUC – 3’ of SEQ ID NO: 3, wherein each strand is about 14 to about 30 nucleotides in length, wherein all of the nucleotides of the sense strand and all of the tides of the antisense strand are modified nucleotides, wherein the sense strand comprises no more than 8 2'-fluoro modifications; wherein the nse strand comprises no more than 6 2'-fluoro modifications; wherein the sense strand and the antisense strand each independently comprise two phosphorothioate linkages at the 5’-terminus; and wherein the sense strand is conjugated to at least one ligand.
2. The double stranded RNAi agent, or salt thereof, of claim 1, wherein the double stranded region is 21-23 nucleotide pairs in length.
3. The double stranded RNAi agent, or salt thereof, of claim 1, wherein the cations on the nucleotides are selected from the group consisting of a deoxy-nucleotide, a 3’-terminal deoxythymine (dT) nucleotide, a 2'-O-methyl modified nucleotide, a oro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2’-amino-modified nucleotide, a 2’-O-allyl-modified nucleotide, 2’-C-alkyl-modified nucleotide, roxlymodified tide, a 2’-methoxyethyl modified nucleotide, a 2’-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a hydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide sing a 5’-phosphate, and a nucleotide comprising a 5’-phosphate mimic, and combinations thereof.
4. The double ed RNAi agent, or salt thereof, of claim 3, wherein the modifications on the tides are 2'-O-methyl or 2'-fluoro modifications. 76_1 ters) P107927.NZ
5. The double ed RNAi agent, or salt thereof, of claim 1, wherein the sense strand ses no more than 6 2'-fluoro modifications.
6. The double stranded RNAi agent, or salt thereof, of claim 1, wherein the sense strand comprises no more than 5 2'-fluoro modifications.
7. The double stranded RNAi agent, or salt thereof, of claim 1, wherein the sense strand comprises no more than 4 2'-fluoro modifications.
8. The double ed RNAi agent, or salt thereof, of claim 1, wherein the antisense strand comprises no more than 5 2'-fluoro modifications.
9. The double ed RNAi agent, or salt thereof, of claim 1, wherein the antisense strand comprises no more than 4 2'-fluoro modifications.
10. The double stranded RNAi agent, or salt thereof, of claim 1, wherein the antisense strand comprises no more than 3 oro modifications.
11. The double stranded RNAi agent, or salt thereof, of claim 1, wherein the antisense strand comprises no more than 2 2'-fluoro modifications.
12. The double stranded RNAi agent, or salt f, of claim 1, further comprising a 5’- phosphate or a 5’-phosphate mimic at the 5’ nucleotide of the antisense .
13. The double stranded RNAi agent, or salt thereof, of claim 1, further comprising a 5’- phosphate mimic at the 5’ nucleotide of the antisense strand.
14. The double stranded RNAi agent, or salt thereof, of claim 13, wherein the 5’-phosphate mimic is a 5’-vinyl phosphate (5’-VP).
15. The double stranded RNAi agent, or salt thereof, of claim 1, wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.
16. The double ed RNAi agent, or salt thereof, of claim 1, wherein the ligand is 21510476_1 (GHMatters) P107927.NZ HO OH O H H HO O N N O HO OH O H H HO O N N O O O O HO OH HO O N N O AcHN H H O .
17. The double stranded RNAi agent, or salt thereof, of claim 1, wherein the ligand is attached to the 3' end of the sense strand.
18. The double stranded RNAi agent, or salt thereof, of claim 17, wherein the RNAi agent is ated to the ligand as shown in the following schematic ,wherein X is O or S.
19. The double stranded RNAi agent, or salt thereof, of claim 18, wherein X is O.
20. The double stranded RNAi agent, or salt thereof, of claim 1, wherein the antisense strand comprises a nucleotide sequence selected from the group ting of 5’- usCfsuugguuacaugAfaaucccasusc – 3’ of SEQ ID NO: 6, 5’- usCfsuugGfuuAfcaugAfaAfucccasusc – 3’ of SEQ ID NO: 7, 5’- UfsCfsuugGfuuAfcaugAfaAfucccasusc – 3’ of SEQ ID NO: 8, and 5’- suugGfuuAfcaugAfaAfucccasusc – 3’ of SEQ ID NO: 9, 21510476_1 (GHMatters) P107927.NZ wherein a, c, g, and u are 2'-O-methyl (2'-OMe) A, C, G, and U, respectively; Af, Cf, Gf, and Uf are 2'-fluoro A, C, G, and U, tively; s is a phosphorothioate linkage; and VP is a 5’- phosphate mimic.
21. The double stranded RNAi agent of claim 1, wherein the sense and antisense strands comprise nucleotide sequences ed from the group consisting of (i) 5’- usgsggauUfuCfAfUfguaaccaaga – 3’ of SEQ ID NO: 10 and 5’- ugguuacaugAfaaucccasusc – 3’ of SEQ ID NO: 6; (ii) 5’- usgsggauUfuCfAfUfguaaccaaga – 3’ of SEQ ID NO: 10 and 5’- usCfsuugGfuuAfcaugAfaAfucccasusc – 3’ of SEQ ID NO: 7; (iii) 5’- usgsggauUfuCfAfUfguaaccaaga – 3’ of SEQ ID NO: 10 and 5’- UfsCfsuugGfuuAfcaugAfaAfucccasusc – 3’ of SEQ ID NO: 8; and (iv) 5’- usgsggauUfuCfAfUfguaaccaaga – 3’ of SEQ ID NO: 10 and 5’- VPusCfsuugGfuuAfcaugAfaAfucccasusc – 3’ of SEQ ID NO: 9, wherein a, c, g, and u are 2'-O-methyl (2'-OMe) A, C, G, and U, respectively; Af, Cf, Gf, and Uf are 2'-fluoro A, C, G, and U, tively; s is a phosphorothioate linkage; and VP is a 5’- phosphate mimic.
22. The double stranded RNAi agent, or salt thereof, of claim 1, wherein the antisense strand comprises the tide sequence 5’- usCfsuugGfuuAfcaugAfaAfucccasusc – 3’ of SEQ ID NO: 7, wherein a, c, g, and u are 2'-O-methyl (2'-OMe) A, C, G, and U, respectively; Af, Cf, Gf, and Uf are 2'-fluoro A, C, G, and U, respectively; and s is a phosphorothioate linkage.
23. A pharmaceutical composition comprising the double stranded RNAi agent, or salt thereof, of any one of claims 1-22.
24. The pharmaceutical composition of claim 23, wherein double stranded RNAi agent, or salt thereof, is present in an unbuffered solution.
25. The pharmaceutical ition of claim 24, wherein the unbuffered solution is saline or water.
26. The pharmaceutical composition of claim 23, n the double stranded RNAi agent, or salt thereof, is present in a buffer solution. 21510476_1 (GHMatters) P107927.NZ
27. The pharmaceutical composition of claim 26, wherein the buffer solution comprises acetate, citrate, prolamine, carbonate, or ate or any combination thereof.
28. The pharmaceutical composition of claim 26, n the buffer solution is phosphate buffered saline (PBS).
29. A method for inhibiting expression of transthyretin (TTR) in a cell in vitro, the method comprising: contacting the cell with the double stranded RNAi agent, or salt thereof, of any one of claims 1-22 or the pharmaceutical composition of any one of claims 23-28, thereby inhibiting expression of the TTR gene in the cell.
30. The method of claim 29, wherein the TTR expression is inhibited by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98% or about 100%.
31. Use of the double stranded RNAi agent, or salt thereof, of any one of claims 1-22 or the pharmaceutical composition of any one of claims 23-28, for the manufacture of a medicament for treating a TTR-associated disease in a t.
32. The use of claim 31, wherein the medicament is formulated to reduce, slow, or arrest a Neuropathy Impairment Score (NIS) or a modified NIS (mNIS+7) in the t.
33. The use of claim 31, n the medicament is formulated to increase a te walk test (6MWT) in the subject.
34. The use of any one of claims 31-33, wherein the subject s a TTR gene mutation that is associated with the development of a TTR-associated e.
35. The use of any one of claims 31-33, wherein the TTR-associated disease is ed 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.
36. The use of any one of claims 31-33, wherein the double stranded RNAi agent, or salt thereof, is to be administered to the subject by an administration means selected from the group 21510476_1 (GHMatters) P107927.NZ consisting of subcutaneous, intravenous, uscular, intrabronchial, intrapleural, intraperitoneal, intraarterial, lymphatic, cerebrospinal, and any combinations thereof.
37. The use of claim 36, wherein the double stranded RNAi agent, or salt thereof, is to be administered to the subject via subcutaneous, intramuscular or intravenous administration.
38. The use of claim 37, wherein the double stranded RNAi agent, or salt thereof, is to be administered to the subject via subcutaneous administration.
39. The use of claim 38, wherein the subcutaneous administration is self-administration.
40. The use of claim 39, wherein the self-administration is via a pre-filled e or autoinjector syringe.
41. The use of any one of claims 31-33, n the double stranded RNAi agent, or salt thereof, is to be chronically administered to the subject. 21510476_1 (GHMatters) P107927.NZ U000000000000 Tritosomes 1 /<<<<<<<<<<<<<<<<<<<<<<<<<<<<
NZ739169A 2016-07-28 TRANSTHYRETIN (TTR) iRNA COMPOSITIONS AND METHODS OF USE THEREOF FOR TREATING OR PREVENTING TTR-ASSOCIATED DISEASES NZ739169B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
NZ778442A NZ778442B2 (en) 2016-07-28 Transthyretin (TTR) iRNA compositions and methods of use thereof for treating or preventing TTR-associated diseases

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201562199563P 2015-07-31 2015-07-31
US201662287518P 2016-01-27 2016-01-27
PCT/US2016/044359 WO2017023660A1 (en) 2015-07-31 2016-07-28 TRANSTHYRETIN (TTR) iRNA COMPOSITIONS AND METHODS OF USE THEREOF FOR TREATING OR PREVENTING TTR-ASSOCIATED DISEASES

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