US2009170794A1PendingUtilityA1

Small interfering rnas that efficiently inhibit viral expression and methods of use thereof

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Assignee: SOMAGENICS INCPriority: Sep 10, 2004Filed: Sep 12, 2005Published: Jul 2, 2009
Est. expirySep 10, 2024(expired)· nominal 20-yr term from priority
Inventors:Roger L. KasparHeine IlvesAttila A. SeyhanAlexander VlassovBrian H. Johnston
A61P 31/14C12N 15/1131C12N 2310/111C12N 2310/53C12N 2770/36111C12N 2310/14A61P 1/16C12N 2770/24211
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Claims

Abstract

The invention provides methods, compositions, and kits comprising small interfering RNA (shRNA or siRNA) which are useful for inhibition of viralmediated gene expression. Small interfering RNAs as described herein may be used in methods of treatment of HCV infection. ShRNA and siRNA constructs that target the internal ribosome entry site (IRES) sequence of HCV are described.

Claims

exact text as granted — not AI-modified
1 . A method of inhibiting gene expression in a virus, comprising introducing a small interfering RNA into a virus-containing cell, wherein said small interfering RNA comprises a sequence that is at least partially complementary to a polynucleotide sequence of the virus, wherein interaction of said at least partially complementary sequence of the small interfering RNA with said polynucleotide sequence of the virus results in inhibition of gene expression in the virus. 
     
     
         2 . A method according to  claim 1 , wherein the small interfering RNA is a shRNA. 
     
     
         3 . A method according to  claim 1 , wherein the small interfering RNA is an siRNA. 
     
     
         4 . A method according to any of  claims 1 - 3 , wherein the small interfering RNA recognizes a viral sequence of about 19 to about 30 nucleotides. 
     
     
         5 . A method according to  claim 1 , wherein the virus is a hepatitis C virus. 
     
     
         6 . A method according to  claim 5 , wherein the small interfering RNA interacts with a sequence within the internal ribosome entry site (IRES) sequence of the hepatitis C virus. 
     
     
         7 . A method according to  claim 6 , wherein the IRES sequence comprises the sequence depicted in SEQ ID NO:11. 
     
     
         8 . A method according to  claim 7 , wherein the small interfering RNA recognizes a sequence of about 19 to about 30 nucleotides within the region depicted in SEQ ID NO:26. 
     
     
         9 . A method according to any of  claims 5 - 8 , wherein the small interfering RNA is a shRNA. 
     
     
         10 . A method according to  claim 9 , wherein the shRNA comprises a sequence selected from the group consisting of SEQ ID NO:12, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:27, SEQ ID NO:32, and SEQ ID NO:33. 
     
     
         11 . A method according to  claim 10 , wherein the shRNA has the sequence depicted in SEQ ID NO:12. 
     
     
         12 . A method according to any of  claim 5 - 8 , wherein the small interfering RNA is a siRNA. 
     
     
         13 . A method according to  claim 12 , wherein the siRNA comprises a sequence selected from the group consisting of SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ NO: 23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:32, and SEQ ID NO:33. 
     
     
         14 . A method of treating a viral infection in a mammal, said method comprising administering to the mammal a composition comprising a therapeutically effective amount of a small interfering RNA that comprises a sequence that is at least partially complementary to a polynucleotide sequence of the virus, wherein interaction of said at least partially complementary sequence of the small interfering RNA with said polynucleotide sequence of the virus results in inhibition of gene expression in the virus. 
     
     
         15 . A method according to  claim 14 , wherein the small interfering RNA is an shRNA. 
     
     
         16 . A method according to  claim 14 , wherein the small interfering RNA is an siRNA. 
     
     
         17 . A method according to any of  claims 14 - 16 , wherein the small interfering RNA recognizes a viral sequence of about 19 to about 30 nucleotides. 
     
     
         18 . A method according to  claim 14 , wherein said mammal is a human and the viral infection comprises a hepatitis C virus. 
     
     
         19 . A method according to  claim 18 , wherein the small interfering RNA comprises a sequence that is at least partially complementary to a polynucleotide sequence within the IRES sequence of the hepatitis C virus. 
     
     
         20 . A method according to  claim 19 , wherein the IRES sequence comprises the sequence depicted in SEQ ID NO:11. 
     
     
         21 . A method according to  claim 20 , wherein the small interfering RNA binds recognizes a sequence of about 19 to about 30 nucleotides within the region depicted in SEQ ID NO:26. 
     
     
         22 . A method according to any of  claims 18 - 21 , wherein the small interfering RNA is an shRNA. 
     
     
         23 . A method according to  claim 22 , wherein the shRNA comprises a sequence selected from the group consisting of SEQ ID NO:12, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ NO: 23, SEQ ID NO:24, and SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:32, and SEQ ID NO:33. 
     
     
         24 . A method according to  claim 23 , wherein the shRNA has the sequence depicted in SEQ ID NO:12. 
     
     
         25 . A method according to any of  claim 18 - 21 , wherein the small interfering RNA is a siRNA. 
     
     
         26 . A method according to  claim 25 , wherein the siRNA comprises a sequence selected from the group consisting of SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ NO: 23, SEQ ID NO:24, and SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:32, and SEQ ID NO:33. 
     
     
         27 . A composition comprising a shRNA comprising a sequence selected from the group consisting of SEQ ID NO:12, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ NO: 23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:32, and SEQ ID NO:33. 
     
     
         28 . A composition comprising a siRNA comprising a sequence selected from the group consisting of SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ NO: 23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:27, SEQ ID NO:32, and SEQ ID NO:33. 
     
     
         29 . A pharmaceutical composition comprising a shRNA according to  claim 27  and a pharmaceutically acceptable excipient. 
     
     
         30 . A pharmaceutical composition comprising a siRNA according to  claim 28  and a pharmaceutically acceptable excipient. 
     
     
         31 . A kit comprising a shRNA and instructions for use in a method according to any of  claims 1 ,  5 - 8 ,  14 , and  18 - 21 . 
     
     
         32 . A kit according to  claim 31 , wherein the shRNA comprises a sequence selected from the group consisting of SEQ ID NO:12, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ NO: 23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:32, and SEQ ID NO:33. 
     
     
         33 . A kit comprising a siRNA and instructions for use in a method according to any of  claims 1 ,  5 - 8 ,  14 , and  18 - 21 . 
     
     
         34 . A kit according to  claim 33 , wherein the siRNA comprises a sequence selected from the group consisting of SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ NO: 23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:27, SEQ ID NO:32, and SEQ ID NO:33. 
     
     
         35 . A method according to  claim 18 , wherein said hepatitis C virus is genotype 1a. 
     
     
         36 . A method according to  claim 14 , wherein said mammal is a human.

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