WO2007056153B1 - Peptide-dicer substrate rna conjugates as delivery vehicles for sirna - Google Patents

Peptide-dicer substrate rna conjugates as delivery vehicles for sirna

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Publication number
WO2007056153B1
WO2007056153B1 PCT/US2006/042978 US2006042978W WO2007056153B1 WO 2007056153 B1 WO2007056153 B1 WO 2007056153B1 US 2006042978 W US2006042978 W US 2006042978W WO 2007056153 B1 WO2007056153 B1 WO 2007056153B1
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WIPO (PCT)
Prior art keywords
seq
composition
strand
sirna
nucleotide sequence
Prior art date
Application number
PCT/US2006/042978
Other languages
French (fr)
Other versions
WO2007056153A2 (en
WO2007056153A3 (en
Inventor
Steven C Quay
Paul Hickok Johnson
Michael E Houston Jr
Kunyuan Cui
Mohammad Ahmadian
Lishan Chen
Yuching Chen
Sasha J Mayer
Renata Fam
Original Assignee
Nastech Pharm Co
Steven C Quay
Paul Hickok Johnson
Michael E Houston Jr
Kunyuan Cui
Mohammad Ahmadian
Lishan Chen
Yuching Chen
Sasha J Mayer
Renata Fam
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nastech Pharm Co, Steven C Quay, Paul Hickok Johnson, Michael E Houston Jr, Kunyuan Cui, Mohammad Ahmadian, Lishan Chen, Yuching Chen, Sasha J Mayer, Renata Fam filed Critical Nastech Pharm Co
Priority to EP06836880A priority Critical patent/EP1942943A2/en
Priority to JP2008539062A priority patent/JP2009514877A/en
Priority to AU2006311912A priority patent/AU2006311912A1/en
Priority to CA002628113A priority patent/CA2628113A1/en
Publication of WO2007056153A2 publication Critical patent/WO2007056153A2/en
Publication of WO2007056153A3 publication Critical patent/WO2007056153A3/en
Publication of WO2007056153B1 publication Critical patent/WO2007056153B1/en
Priority to IL191147A priority patent/IL191147A0/en

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    • C12N15/1136—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against growth factors, growth regulators, cytokines, lymphokines or hormones
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    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
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    • C12N15/1131—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against viruses
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    • C12N2320/32—Special delivery means, e.g. tissue-specific

Abstract

Provided are compositions comprising a double stranded ribonucleic acid (dsRNA) molecule and a peptide of about 5 to about 40 amino acids, wherein the dsRNA molecule is conjugated to the peptide. The strands of the dsRNA may have lengths from about 25 to about 30 base pairs, which may be the same or different. siRNA may, alternatively, comprise at least three strands (i.e., either at least two sense strands and one antisense strand or at least two antisense strands and one sense strand) wherein the at least two sense strands or the at least two antisense strands are separated by a nick or a gap of at least one nucleotide.

Claims

84AMENDED CLAIMS [received by the International Bureau on 14 September 2007 (14.09.2007)]CLAIMS
1. A composition comprising:
(a) a double stranded ribonucleic acid (dsRNA) molecule, wherein the strands have lengths from about 25 to about 30 nucleotides which may be the same or different; and
(b) a peptide comprising about 5 to about 40 amino acids, wherein the peptide contains the amino acid sequence KVLKQ (SEQ ID NO: 51); wherein the dsRNA molecule is conjugated to the peptide.
2. The composition of claim 1, wherein the dsRNA molecule is an siRNA.
3. The composition of claim 2, wherein the siRNA contains a nucleic sequence homologous to a portion of the nucleic sequence of a human TNF-alpha gene.
4. The composition of claim 2, wherein the siRNA contains a nucleic sequence homologous to a portion of the nucleic sequence of a viral gene.
5. The composition of claim 4, wherein the source of the viral gene is an influenza virus.
6. The composition of claim 1, further comprising a carrier.
7. The composition of claim 1, wherein the dsRNA molecule further comprises a single stranded 3' antisense strand overhang comprising 2 nucleotides.
8. The composition of claim 1, wherein the dsRNA molecule further comprises a single stranded 3' sense strand overhang comprising 2 nucleotides.
9. The composition of claim 1, wherein the dsRNA molecule has no overhang.
10. The composition of claim 1, wherein the strands have lengths from about 25 to about 29 nucleotides which may be the same or different. 85
11. The composition of claim 1, wherein the dsRNA molecule consists of a sense RNA strand and an antisense RNA strand, and the peptide is conjugated to the 5' end of the antisense RNA strand.
12. The composition of claim 1, wherein the amino acid sequence of the peptide is selected from the group consisting of:
KGSKKAVTKAQKKDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 33); KKAVTKAQKKDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 42); VTKAQKKDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 43); AQKKDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 44); KDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 45); KKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 46); KRSRKESYSVYVYKVLKQ (SEQ ID NO: 47);
RKESYSVYVYKVLKQ (SEQ ID NO: 41); SYSVYVYKVLKQ (SEQ ID NO: 48); VYVYKVLKQ (SEQ ID NO: 49); YKVLKQ (SEQ ID NO: 50); and
KVLKQ (SEQ ID NO: 51).
13. The composition of claim 1, wherein the peptide is conjugated to a molecule that binds to a cell in an animal.
14. Use of the composition as in any one of claims 1-3 or 6-13 for ameliorating inflammation associated with TNF-α comprising administering an ameliorating amount of the composition to an animal.
15. Use of the composition as in any one of claims 1-3 or 6-13 in the manufacture of a medicament for ameliorating inflammation associated with TNF-α in an animal.
16. The use of claims 14 or 15, wherein the inflammation occurs in arthritis.
17. The use of claims 14 or 15, wherein the inflammation occurs in psoriasis.
18. Use of a pharmaceutical composition for inhibiting expression of a gene in an animal for ameliorating inflammation comprising administering a double stranded ribonucleic acid (dsRNA) molecule to the animal, wherein the pharmaceutical 86
composition comprises the dsRNA molecule and a peptide, wherein the dsRNA molecule comprises about 25 to about 30 base pairs, wherein the peptide comprises about 5 to about 40 amino acids and comprises the amino acid sequence KVLKQ (SEQ ID NO: 51), and wherein the dsRNA molecule is conjugated to the peptide.
19. Use of a pharmaceutical composition comprising a double stranded ribonucleic acid (dsRNA) molecule and a peptide in the manufacture of a medicament for inhibiting expression of a gene in an animal for ameliorating inflammation , wherein the dsRNA molecule comprises about 25 to about 30 base pairs, wherein the peptide comprises about 5 to about 40 amino acids and comprises the amino acid sequence KVLKQ (SEQ ID NO: 51), and wherein the dsRNA molecule is conjugated to the peptide.
20. The use of claims 18 or 19, wherein the inflammation occurs in arthritis.
21. The use of claims 18 or 19, wherein the inflammation occurs in psoriasis.
22. Use of the composition of claim 1 for ameliorating infection associated with influenza virus comprising administering an ameliorating amount of the composition to an animal.
23. Use of the composition of claim 1 in the manufacture of a medicament for ameliorating infection associated with influenza virus in an animal.
24. A composition comprising:
(a) a small inhibitory nucleic acid (siRNA) molecule, the siRNA molecule comprising a first RNA strand (A strand) of between about 15 nucleotides and about 50 nucleotides, a second RNA strand (Bl strand) of between about between about 1 nucleotide and about 25 nucleotides, and a third RNA strand (B2 strand) of between about 1 nucleotide and about 25 nucleotides; wherein the dsRNA molecule is conjugated to the peptide. wherein the Bl strand and the B2 strand are each complementary to non- overlapping regions of the A strand; wherein a first double-stranded region (A:B1) is formed by annealing the Bl strand and the A strand; and 87
wherein a second double-stranded region (A:B2) is formed by annealing the B2 strand and the A strand; and
(b) a peptide comprising about 5 to about 40 amino acids, wherein the siRNA molecule is conjugated to the peptide.
25. The composition of claim 24 wherein the A:B1 duplex is separated from the A:B2 duplex by a nick or by a gap wherein the gap results from at least one unpaired nucleotide in the A strand that is positioned between the A:B 1 duplex and the A:B2 duplex.
26. The composition of claim 25 further comprising one or more unpaired nucleotide(s) at the 3' end of either or both of the A strand, the Bl strand, and/or the B2 strand.
27. The composition of any of claims 25-26 wherein the A strand is between about 18 nucleotides and about 40 nucleotides.
28. The composition of claim 27 wherein the A strand is between about 20 nucleotides and about 32 nucleotides.
29. The composition of claim 28 wherein the A strand is 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 nucleotides.
30. The composition of any one of claims 25-26 wherein the A:B1 duplex and the A:B2 duplex comprise, in sum, between about 15 base-pairs and about 40 base-pairs.
31. The composition of claim 30 wherein the A:B1 duplex and the A:B2 duplex comprise, in sum, between about 18 base-pairs and about 35 base-pairs.
32. The composition of claim 31 wherein the A:B1 duplex and the A:B2 duplex comprise, in sum, between about 20 base-pairs and about 30 base-pairs.
33. The composition of claim 32 wherein the A:B1 duplex and the A:B2 duplex comprise, in sum, either 21, 22, 23, 24, 25, 26, 27, 28, or29 base-pairs. 88
34. The composition of claim 26 wherein the siRNA molecule comprises one or two single-strand 3' overhang(s) of between 1 nucleotide and 5 nucleotides.
35. The composition of any one of claims 25-26 wherein the A strand comprises the nucleotide sequence 3TTCCUAGAAUAAAGAAGCCUCUGUUACS' (SEQ ID NO: 76).
36. The composition of claim 22 wherein the Bl strand comprises the nucleotide sequence 5'GGAUCU3' (SEQ ID NO: 77).
37. The composition of claim 25 wherein the B2 strand comprises the nucleotide sequence 5ACAAUG31 (SEQ ID NO: 90).
38. The composition of claim 25 wherein the A:B1 duplex is separated from the A:B2 duplex by a nick.
39. The composition of claim 38 wherein the B2 strand terminates with a 5' hydroxyl.
40. The composition of claim 38 wherein the Bl strand comprises the nucleotide sequence 51GGAUCUU AUUU3' (SEQ ID NO: 135), wherein the B2 strand comprises the nucleotide sequence 5'CUUCGGAGTT3' (SEQ ID NO: 136), and wherein the A strand comprises the nucleotide sequence 5'CUCCGAAGAAAUAAGAUCCTTS' (SEQ ID NO: 137).
41. The composition of claim 38 wherein the Bl strand comprises the nucleotide sequence 5'GGATCTTATTT3' (SEQ ID NO: 144), wherein the B2 strand comprises the nucleotide sequence 5'CTTCGGAGTT3' (SEQ ID NO: 145), and wherein the A strand comprises the nucleotide sequence 5 'CTCCG AAGAAAT AAGATCCTT31 (SEQ ID NO: 146).
42. The composition of claim 38 wherein the Bl strand comprises the nucleotide sequence 5'CTCCGAAGAA3' (SEQ ID NO: 148), wherein the B2 strand comprises the nucleotide sequence 5ΑTAAGATCCTT3' (SEQ ID NO: 149), and wherein the A strand comprises the nucleotide sequence 5'GGATCTTATT TCTTCGGAGTT3' (SEQ ID NO: 147). 89
43. The composition of claim 38 wherein the Bl strand comprises the nucleotide sequence 51GGAUCUUAUUUS' (SEQ ID NO: 153), wherein the B2 strand comprises the nucleotide sequence 51CUUCGGAGTTS1 (SEQ ID NO: 154), and wherein the A strand comprises the nucleotide sequence 5'CUCCGAAGAAAUAAGAUCCTTS' (SEQ ID NO: 155).
44. The composition of claim 38 wherein the Bl strand comprises the nucleotide sequence 5'GGATCTT ATTT3' (SEQ ID NO: 159), wherein the B2 strand comprises the nucleotide sequence 5'CTTCGGAGTT3' (SEQ ID NO: 160), and wherein the A strand comprises the nucleotide sequence 5 'CTCCGAAGAAAT AAGATCCTT3' (SEQ ID NO: 161).
45. The composition of claim 38 wherein the Bl strand comprises the nucleotide sequence 5 'CTCCGAAG AA3' (SEQ ID NO: 166), wherein the B2 strand comprises the nucleotide sequence 5'ATAAGATCCTTS1 (SEQ ID NO: 34), and wherein the A strand comprises the nucleotide sequence 5'GGATCTTATT TCTTCGGAGTT3' (SEQ ID NO: 165).
46. The composition of claim 38 wherein the Bl strand terminates with a 5' phosphate.
47. The composition of claim 46 wherein the Bl strand comprises the nucleotide sequence 5'GGAUCUU AUUU3' (SEQ ID NO: 138), wherein the B2 strand comprises the nucleotide sequence 5'CUUCGGAGTTS1 (SEQ ID NO: 139), and wherein the A strand comprises the nucleotide sequence 5'CUCCGAAGAAAUAAGAUCCTTS' (SEQ ID NO: 140).
48. The composition of claim 46 wherein the Bl strand comprises the nucleotide sequence 5'GGATCTTATTT3' (SEQ ID NO: 141), wherein the B2 strand comprises the nucleotide sequence 5'CTTCGGAGTT3' (SEQ ID NO: 142), and wherein the A strand comprises the nucleotide sequence 51CTCCGAAGAAATAAGATCCTTS' (SEQ ID NO: 143). 90
49. The composition of claim 46 wherein the Bl strand comprises the nucleotide sequence 51CTCCGAAGAAS' (SEQ ID NO: 151), wherein the B2 strand comprises the nucleotide sequence 5ΑTAAGATCCTT3' (SEQ ID NO: 152), and wherein the A strand comprises the nucleotide sequence 5' GGATCTTATTTCTTCGGAGTT 3' (SEQ ID NO: 150).
50. The composition of claim 46 wherein the Bl strand comprises the nucleotide sequence 5'GGAUCUU AUUU3' (SEQ ID NO: 156), wherein the B2 strand comprises the nucleotide sequence 5'CUUCGGAGTT3? (SEQ ID NO: 157), and wherein the A strand comprises the nucleotide sequence 5'CUCCGAAGAAAUAAGAUCCTTS' (SEQ ID NO: 158).
51. The composition of claim 46 wherein the Bl strand comprises the nucleotide sequence 5'GGATCTTATTT3' (SEQ ID NO: 162), wherein the B2 strand comprises the nucleotide sequence 5'CTTCGGAGTT3' (SEQ ID NO: 163), and wherein the A strand comprises the nucleotide sequence 5'CTCCGAAGAAATAAGATCCTT3I (SEQ ID NO: 164).
52. The composition of claim 46 wherein the Bl strand comprises the nucleotide sequence 5'CTCCGAAGAA3' (SEQ ID NO: 39), wherein the B2 strand comprises the nucleotide sequence 5'ATAAGATCCTTS' (SEQ ID NO: 40), and wherein the A strand comprises the nucleotide sequence 5'GGATCTTATTTCTTCGGAGTTS' (SEQ ID NO: 38).
53. A composition comprising:
(a) a small inhibitory nucleic acid (siRNA) molecule, the siRNA molecule comprising three strands A, Bl, and B2 (A:B1B2); wherein A:B1B2 comprises between about 14 total base-pairs and about 24 total base-pairs; wherein A represents the sense strand and B1B2 represents the antisense strand; wherein A is between about 19 nucleotides and about 25 nucleotides; wherein Bl and B2 are each, individually, between about 1 nucleotide and about 15 nucleotides; and 91
wherein the combined length of Bl and B2 is between about 13 nucleotides and about 23 nucleotides; and
(b) a peptide comprising about 5 to about 40 amino acids, wherein the siRNA molecule is conjugated to the peptide.
54. A composition comprising:
(a) a small inhibitory nucleic acid (siRNA) molecule, the siRNA molecule comprising three strands A, Bl, and B2 (A:B1B2); wherein A:B1B2 comprises between about 16 total base-pairs and about 22 total base-pairs; wherein A represents the sense strand and B1B2 represents the antisense strand; wherein A is between about 19 nucleotides and about 23 nucleotides; wherein Bl and B2 are each, individually, between about 1 nucleotide and about 15 nucleotides; and wherein the combined length of Bl and B2 is between about 13 nucleotides and about 23 nucleotides; and
(b) a peptide comprising about 5 to about 40 amino acids, wherein the siRNA molecule is conjugated to the peptide.
55. A composition comprising:
(a) a small inhibitory nucleic acid (siRNA) molecule, the siRNA molecule comprising three strands A, Bl, and B2 (A:B1B2); wherein A:B1B2 comprises between about 14 total base-pairs and about 24 total base-pairs; wherein A represents the antisense strand and B1B2 represents the sense strand; wherein A is between about 14 nucleotides and about 24 nucleotides; wherein Bl and B2 are each, individually, between about 1 nucleotide and about 15 nucleotides; and wherein the combined length of Bl and B2 is between about 18 nucleotides and about 24 nucleotides; and
(b) a peptide comprising about 5 to about 40 amino acids, wherein the siRNA molecule is conjugated to the peptide.
56. A composition comprising:
(a) a small inhibitory nucleic acid (siRNA) molecule, the siRNA molecule comprising three strands A, Bl, andB2 (A:B1B2); wherein A:B1B2 comprises between about 14 total base-pairs and about 22 total base-pairs; wherein A represents the antisense strand and B1B2 represents the sense strand; wherein A is between about 16 nucleotides and about 22 nucleotides; wherein Bl and B2 are each, individually, between about 1 nucleotide and about 15 nucleotides; wherein the combined length of Bl and B2 is between about 18 nucleotides and about 22 nucleotides; and
(b) a peptide comprising about 5 to about 40 amino acids, wherein the siRNA molecule is conjugated to the peptide.
57. A composition comprising:
(a) an siRNA molecule as in any one of claims 24 and 53-56 wherein the siRNA molecule is effective in reducing the titer of a target virus selected from the group consisting of a retrovirus, a respiratory viruses, a human metapneumovirus, a human parainfluenza virus, and an influenza virus; and
(b) a peptide comprising about 5 to about 40 amino acids, wherein the siRNA molecule is conjugated to the peptide.
58. The composition as in any one of claims 24, and 53-56 wherein the peptide comprises an amino acid sequence selected from the group consisting of KRRQR-RR (SEQ ID NO: 1), RQIKIWFQNRRMKWKK (SEQ ID NO: 2), DAATATRGRSAASRPTERPRAPARSASRPRRPVD (SEQ ID NO: 3), AAVALLPAVLLALLAP (SEQ ID NO: 4), AAVLLPVLLPVLLAAP (SEQ ID NO: 5), VTVLALGALAGVGVG (SEQ ID NO: 6), GALFLGWLGAAGSTMGA (SEQ ID NO: 7), MGLGLHLLVLAAALQGA (SEQ ID NO: 8), LGTYTQDFNKFHTFPQTAIGVGAP (SEQ ID NO: 9), GWTLNS AGYLLIONLKALAALAKKIL (SEQ ID NO: 10), TPPKKKRKVEDPKKKK (SEQ ID NO: 11), RRRRRRR (SEQ ID NO: 12), KLALKLALKALKAALKLA (SEQ ID NO: 13), GLFGAIAGFIENGWEG (SEQ ID 93
NO: 14), FFGAVIGTIALGVATA (SEQ ID NO: 15), FLGFLLGVGSAIASGV (SEQ ID NO: 16), GVFVLGFLGFLATAGS (SEQ ID NO: 17), GAAIGLAWIPYFGPAA (SEQ ID NO: 18),
ACTCPYCKDSEGRGSGDPGKKKQHICHIQGCGKVYGKTSHLRAHLRWHTGERPF MC (SEQ ID NO: 19),
ACTCPNCKDGEKRSGEQGKKKHVCHIPDCGKTFRKTSLLRAHVRLHTGERPFVC (SEQ ID NO: 20),
ACTCPNCKEGGGRGTNLGKKKQHICHIPGCGKVYGKTSHLRAHLRWHSGERPF VC (SEQ ID NO: 21),
ACSCPNCREGEGRGSNEPGKKKQHICHIEGCGKVYGKTSHLRAHLRWHTGERPF IC (SEQ ID NO: 22),
RCTCPNCTNEMSGLPPIVGPDERGRKQHICHIPGCERLYGKASHLKTHLRWHTGE RPFLC (SEQ ID NO: 23),
TCDCPNCQEAERLGPAGVHLRKKNIHSCHIPGCGKVYGKTSHLKAHLRWHTGER PFVC (SEQ ID NO: 24),
RCTCPNCKAIKHGDRGSQHTHLCSVPGCGKTYKKTSHLRAHLRKHTGDRPFVC (SEQ ID NO: 25),
PQISLKKKIFFFIFSNFRGDGKSRIHICHLCNKTYGKTSHLRAHLRGHAGNKPFAC (SEQ ID NO: 26),
WWETWKPFQCRICMRNFSTRQARRNHRRRHR (SEQ ID NO: 27), GKINLKALAALAKKIL (SEQ ID NO: 28), RVIRVWFQNKRCKDKK (SEQ ID NO: 29), GRKIOtRQRRRPPQGRKKRRQRRRPPQGRKKRRQRRRPPQ (SEQ ID NO: 30), GEQIAQLIAGYIDIILKKKKSK (SEQ ID NO: 31),
KGSI<-KAVTKAQKKI)GKK-W<IISRKESYSVYVYKVLKQ (SEQ ID NO: 33), KGSKKAVTKAQKKDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 37), RKESYSVYVYKVLKQ (SEQ ID NO: 41),
KKAVTKAQKIΦGIζKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 42), VTKAQKKDGICKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 43), AQKKDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 44), KDGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 45), KKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 46), 94
KRSRKESYSVYVYKVLKQ (SEQ ID NO: 47), SYSVYVYKVLKQ (SEQ ID NO: 48), VYVYKVLKQ (SEQ ID NO: 49), YKVLKQ (SEQ ID NO: 50), KVLKQ (SEQ ID NO: 51), and KGSE.KAVTKAQKKEGKKRKRSRKESYSVYVYKVLKQ (SEQ ID NO: 52).
59. Use of an siRNA molecule for reducing the titer of a target virus, the use comprising the steps of:
(a) selecting a target gene for siRNA-mediated gene silencing wherein the target gene is a target viral gene;
(b) designing and/or synthesizing a suitable siRNA molecule(s) for siRNA mediated gene silencing of the target viral gene, wherein each of the siRNA molecule(s) comprises a gapped or nicked duplex and wherein the gap or nick appears in either a sense strand or in an anti-sense strand of the siRNA duplex;
(c) conjugating the siRNA to a peptide comprising about 5 to about 40 amino acids; and
(d) administering the siRNA molecule(s) to a cell expressing the target viral gene, wherein the siRNA molecule peptide conjugate is capable of specifically binding to the corresponding target viral mRNA thereby reducing its expression level in the cell.
60. Use of an siRNA molecule(s) for the manufacture of a medicament for reducing the titer of a target virus by siRNA-mediated gene silencing of a target viral gene, wherein each of the siRNA molecule(s) comprises a gapped or nicked duplex and wherein the gap or nick appears in either a sense strand or in an anti-sense strand of the siRNA duplex; wherein the siRNA is conjugated to a peptide comprising about 5 to about 40 amino acids; and wherein the siRNA molecule peptide conjugate is capable of specifically binding to the corresponding target viral mRNA thereby reducing its expression level in the cell.
61. Use of an siRNA molecule for reducing the expression of an endogenous gene, the use comprising the steps of:
(a) selecting a target gene for siRNA-mediated gene silencing wherein the target gene is an endogenous gene; 95
(b) designing and/or synthesizing a suitable gapped or nicked duplex siRNA molecule(s) for siRNA mediated gene silencing of the endogenous target gene wherein the siRNA molecule comprises a gapped or nicked duplex and wherein the gap or nick appears in either the sense strand or in the anti-sense strand of the siRNA molecule; and
(c) conjugating the siRNA to a peptide comprising about 5 to about 40 amino acids; and
(d) administering the siRNA molecule to a cell expressing the endogenous target gene, wherein the siRNA molecule peptide conjugate is capable of specifically binding to the corresponding endogenous target mRNA thereby reducing its expression level in the cell.
62. Use of an siRNA molecule(s) for the manufacture of a medicament for reducing the expression of an endogenous gene by siRNA mediated gene silencing of the endogenous target gene, wherein the siRNA molecule comprises a gapped or nicked duplex and wherein the gap or nick appears in either the sense strand or in the anti-sense strand of the siRNA molecule; and wherein the siRNA is conjugated to a peptide comprising about 5 to about 40 amino acids; and wherein the siRNA molecule peptide conjugate is capable of specifically binding to the corresponding endogenous target mRNA thereby reducing its expression level in the cell.
63. The composition of any of claims 1-13 or 24-58 for use in medicine.
64. The composition in any one of claims 1-3 or 6-13 for use as a medicament for ameliorating inflammation associated with TNF-α.
65. The composition of claim 64 wherein the inflammation occurs in arthritis.
66. The composition of claim 64 wherein the inflammation occurs in psoriasis.
67. The composition of claim 1 for use as a medicament for ameliorating infectionassociated with influenza virus.
PCT/US2006/042978 2005-11-04 2006-11-03 Peptide-dicer substrate rna conjugates as delivery vehicles for sirna WO2007056153A2 (en)

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AU2006311912A AU2006311912A1 (en) 2005-11-04 2006-11-03 Peptide-dicer substrate RNA conjugates as delivery vehicles for siRNA
CA002628113A CA2628113A1 (en) 2005-11-04 2006-11-03 Peptide-dicer substrate rna conjugates as delivery vehicles for sirna
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