Oligonucleotide Therapeutics

Part of the Cancer Drug Discovery and Development book series (CDD&D)


The idea of sequence-specific gene silencing by synthetic oligonucleotides targeting mRNA is at least 40 years old, but it was only in the mid-1980s when technical advances made the chemical synthesis of oligonucleotides possible that practical steps could be taken toward its implementation. The result was a deluge of experimental data in a variety of systems [1], most of which employed the phosphorothioate (PS) backbone modification, and much of which was ultimately, and unfortunately, uninterpretable.


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  1. 1.
    Stein CA, Cheng YC: Antisense oligonucleotides as therapeutic agents: is the bullet really magical? Science 261:1004–1012, 1993PubMedCrossRefGoogle Scholar
  2. 2.
    Stec WJ, Zon G, Egan W, et al: Automated solid-phase synthesis, separation and stereochemistry of phosphorothioate analogs of oligodeoxyribonucleotides. J Am Chem Soc 106:6077–6079, 1984CrossRefGoogle Scholar
  3. 3.
    Eder PS, DeVine RJ, Dagle JM, et al: Substrate specificity and kinetics of degradation of ­antisense oligonucleotides by a 3′ exonuclease in plasma. Antisense Res Dev 1:141–151, 1991PubMedGoogle Scholar
  4. 4.
    Stein CA, Subasinghe C, Shinozuka K, et al: Physicochemical properties of phosphorothioate oligodeoxynucleotides. Nucleic Acids Res 16:3209–3221, 1988PubMedCrossRefGoogle Scholar
  5. 5.
    Watanabe TA, Geary RS, Levin AA: Plasma protein binding of an antisense oligonucleotide targeting human ICAM-1 (ISIS 2302). Oligonucleotides 16:169–180, 2006PubMedCrossRefGoogle Scholar
  6. 6.
    Geary RS, Watanabe TA, Truong L, et al: Pharmacokinetic properties of 2′-O-(2-methoxyethyl)-modified oligonucleotide analogs in rats. J Pharmacol Exp Ther 296:890–897, 2001PubMedGoogle Scholar
  7. 7.
    Geary RS, Yu RZ, Watanabe T, et al: Pharmacokinetics of a tumor necrosis factor-alpha phosphorothioate 2′-O-(2-methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 31:1419–1428, 2003PubMedCrossRefGoogle Scholar
  8. 8.
    Walder RY, Walder JA: Role of RNase H in hybrid-arrested translation by antisense oligonucleotides. Proc Natl Acad Sci USA 85:5011–5015, 1988PubMedCrossRefGoogle Scholar
  9. 9.
    Stein CA, Hansen B, Lai J, et al: Efficient gene silencing by delivery of locked nucleic acid antisence oligonucleotides, unassisted by transfection reagents. Nucl. Acids Res. 2009, doi:  10,1093/nar/gkp841
  10. 10.
    Koshkin AA, Singh SK, Nielsen P, et al: LNA (locked nucleic acids): synthesis of the adenine, cytosine, guanine, 5-methylcytosine, thymine and uracil bicyclonucleoside monomers, oligomerisation and unprecedented nucleic acid recognition. Tetrahedron 54:3607–3630, 1998CrossRefGoogle Scholar
  11. 11.
    Singh SK, Nielsen P, Koshkin AA, et al: LNA (locked nucleic acids): synthesis and high-affinity nucleic acid recognition. Chem Commun (Camb) 4:455–456, 1998CrossRefGoogle Scholar
  12. 12.
    Grünweller A, Wyszko E, Bieber B, et al: Comparison of different antisense strategies in mammalian cells using locked nucleic acids, 2′-O-methyl RNA, phosphorothioates and small interfering RNA. Nucleic Acids Res 31:3185–3193, 2003PubMedCrossRefGoogle Scholar
  13. 13.
    Fluiter K, Frieden M, Vreijling J, et al: On the in vitro and in vivo properties of four locked nucleic acid nucleotides incorporated into an anti-H-Ras antisense oligonucleotide. Chembiochem 6:1104–1109, 2005PubMedCrossRefGoogle Scholar
  14. 14.
    Elayadi AN, Braasch DA, Corey DR: Implications of high-affinity hybridization by locked nucleic acid oligomers for inhibition of human telomerase. Biochemistry 41:9973–9981, 2002PubMedCrossRefGoogle Scholar
  15. 15.
    Braasch DA, Liu Y, Corey DR: Antisense inhibition of gene expression in cells by oligonucleotides incorporating locked nucleic acids: effect of mRNA target sequence and chimera design. Nucleic Acids Res 30:5160–5167, 2002PubMedCrossRefGoogle Scholar
  16. 16.
    Monteith DK, Henry SP, Howard RB, et al: Immune stimulation – a class effect of phosphorothioate oligodeoxynucleotides in rodents. Anticancer Drug Des 12:421–432, 1997PubMedGoogle Scholar
  17. 17.
    Gekeler V, Gimmnich P, Hofmann HP, et al: G3139 and other CpG-containing immunostimulatory phosphorothioate oligodeoxynucleotides are potent suppressors of the growth of human tumor xenografts in nude mice. Oligonucleotides 16:83–93, 2006PubMedCrossRefGoogle Scholar
  18. 18.
    Klasa RJ, Gillum AM, Klem RE, et al: Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment. Antisense Nucleic Acid Drug Dev 12:193–213, 2002PubMedCrossRefGoogle Scholar
  19. 19.
    Kitada S, Takayama S, De Riel K, et al: Reversal of chemoresistance of lymphoma cells by antisense-mediated reduction of bcl-2 gene expression. Antisense Res Dev 4:71–79, 1994PubMedGoogle Scholar
  20. 20.
    Gjertsen BT, Bredholt T, Anensen N, et al: Bcl-2 antisense in the treatment of human malignancies: a delusion in targeted therapy. Curr Pharm Biotechnol 8:373–381, 2007PubMedCrossRefGoogle Scholar
  21. 21.
    Webb A, Cunningham D, Cotter F, et al: BCL-2 antisense therapy in patients with non-Hodgkin lymphoma. Lancet 349:1137–1141, 1997PubMedCrossRefGoogle Scholar
  22. 22.
    Waters JS, Webb A, Cunningham D, et al: Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin’s lymphoma. J Clin Oncol 18:1812–1823, 2000PubMedGoogle Scholar
  23. 23.
    O’Brien S, Moore JO, Boyd TE, et al: Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 25:1114–1120, 2007PubMedCrossRefGoogle Scholar
  24. 24.
    O’Brien S, Moore JO, Boyd TE, et al: 5-year survival in patients with relapsed or refractory CLL in randomized Phase III trial of fludarabine plus cyclophosphamide with or without oblimersen: the Oblimersen CLL Study Group. J. Clin. Oncol. 27:5208–5212, 2009Google Scholar
  25. 25.
    Rai KR, Moore J, Wu J, et al: Effect of the addition of oblimersen (Bcl-2 antisense) to fludarabine/cyclophosphamide for relapsed/refractory chronic lymphocytic leukemia (CLL) on survival in patients who achieve CR/nPR: five-year follow-up from a randomized phase III study. J Clin Oncol 26:374s, 2008 (suppl; abstr 7008)CrossRefGoogle Scholar
  26. 26.
    Weiss LM, Warnke RA, Sklar J, et al: Molecular analysis of the t(14;18) chromosomal translocation in malignant lymphomas. N Engl J Med 317:1185–1189, 1987PubMedCrossRefGoogle Scholar
  27. 27.
    Reed JC, Kitada S, Takayama S, et al: Regulation of chemoresistance by the bcl-2 oncoprotein in non-Hodgkin’s lymphoma and lymphocytic leukemia cell lines. Ann Oncol 5:61–65, 1994PubMedCrossRefGoogle Scholar
  28. 28.
    Schmitt CA, Rosenthal CT, Lowe SW: Genetic analysis of chemoresistance in primary murine lymphomas. Nat Med 6:1029–1035, 2000PubMedCrossRefGoogle Scholar
  29. 29.
    Gazitt Y, Hu WX: Fas (APO-1/CD95)-mediated apoptosis is independent of bcl-2: a study with cell lines overexpressing bcl-2 and with bcl-2 transfected cell lines. Int J Oncol 12:211–220, 1998PubMedGoogle Scholar
  30. 30.
    Gleave ME, Miayake H, Goldie J, et al: Targeting bcl-2 gene to delay androgen-independent progression and enhance chemosensitivity in prostate cancer using antisense bcl-2 oligodeoxynucleotides. Urology 54:36–46, 1999PubMedCrossRefGoogle Scholar
  31. 31.
    Blagosklonny MV: Paradox of Bcl-2 (and p53): why may apoptosis-regulating proteins be irrelevant to cell death? Bioessays 23:947–953, 2001PubMedCrossRefGoogle Scholar
  32. 32.
    Soengas MS, Capodieci P, Polsky D, et al: Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 409:207–211, 2001PubMedCrossRefGoogle Scholar
  33. 33.
    Bush JA, Li G: The role of Bcl-2 family members in the progression of cutaneous melanoma. Clin Exp Metastasis 20:531–539, 2003PubMedCrossRefGoogle Scholar
  34. 34.
    Leiter U, Schmid RM, Kaskel P, et al: Antiapoptotic bcl-2 and bcl-xL in advanced malignant melanoma. Arch Dermatol Res 292:225–232, 2000PubMedCrossRefGoogle Scholar
  35. 35.
    Tang L, Tron VA, Reed JC, et al: Expression of apoptosis regulators in cutaneous malignant melanoma. Clin Cancer Res 4:1865–1871, 1998PubMedGoogle Scholar
  36. 36.
    Ramsay JA, From L, Kahn HJ: bcl-2 protein expression in melanocytic neoplasms of the skin. Mod Pathol 8:150–154, 1995PubMedGoogle Scholar
  37. 37.
    Saenz-Santamaria MC, Reed JA, et al: Immunohistochemical expression of BCL-2 in melanomas and intradermal nevi. J Cutan Pathol 21:393–397, 1994PubMedCrossRefGoogle Scholar
  38. 38.
    Tron VA, Krajewski S, Klein-Parker H, et al: Immunohistochemical analysis of Bcl-2 protein regulation in cutaneous melanoma. Am J Pathol 146:643–650, 1995PubMedGoogle Scholar
  39. 39.
    Plettenberg A, Ballaun C, Pammer J, et al: Human melanocytes and melanoma cells constitutively express the Bcl-2 proto-oncogene in situ and in cell culture. Am J Pathol 146:651–659, 1995PubMedGoogle Scholar
  40. 40.
    Cerroni L, Soyer HP, Kerl H: bcl-2 protein expression in cutaneous malignant melanoma and benign melanocytic nevi. Am J Dermatopathol 17:7–11, 1995PubMedCrossRefGoogle Scholar
  41. 41.
    Jansen B, Wacheck V, Heere-Ress E, et al: Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet 356:1728–1733, 2000PubMedCrossRefGoogle Scholar
  42. 42.
    Bedikian AY, Millward M, Pehamberger H, et al: Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol 24:4738–4745, 2006PubMedCrossRefGoogle Scholar
  43. 43.
    Manola J, Atkins M, Ibrahim J, et al: Prognostic factors in metastatic melanoma: a pooled analysis of Eastern Cooperative Oncology Group trials. J Clin Oncol 18:3782–3793, 2000PubMedGoogle Scholar
  44. 44.
    Agarwala S, Gilles E, Wu J, et al: LDH correlation with survival in advanced melanoma from two large, randomized trials: Oblimersen (GM 301) and EORTC 18951. Eur. J. Cancer 45:1807–1814, 2009Google Scholar
  45. 45.
    Cairns RA, Kalliomaki T, Hill RP: Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors. Cancer Res 61:8903–8908, 2001PubMedGoogle Scholar
  46. 46.
    Postovit LM, Adams MA, Lash GE, et al: Oxygen-mediated regulation of tumor cell invasiveness. Involvement of a nitric oxide signaling pathway. J Biol Chem 277:35730–35737, 2002PubMedCrossRefGoogle Scholar
  47. 47.
    Rofstad EK, Rasmussen H, Galappathi K, et al: Hypoxia promotes lymph node metastasis in human melanoma xenografts by up-regulating the urokinase-type plasminogen activator receptor. Cancer Res 62:1847–1853, 2002PubMedGoogle Scholar
  48. 48.
    Bottaro DP, Liotta LA: Out of air is not out of action. Nature 423:593–595, 2003PubMedCrossRefGoogle Scholar
  49. 49.
    Pennacchietti S, Michieli P, Galluzzo M, et al: Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3:347–361, 2003PubMedCrossRefGoogle Scholar
  50. 50.
    Höckel M, Vaupel P: Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93:266–276, 2001PubMedCrossRefGoogle Scholar
  51. 51.
    Avril MF, Aamdal S, Grob JJ, et al: Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 22:1118–1125, 2004PubMedCrossRefGoogle Scholar
  52. 52.
    Chapman PB, Einhorn LH, Meyers ML, et al: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17:2745–2751, 1999PubMedGoogle Scholar
  53. 53.
    Eton O, Legha SS, Bedikian AY, et al: Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol 20:2045–2052, 2002PubMedCrossRefGoogle Scholar
  54. 54.
    Rudin CM, Salgia R, Wang X, et al: Randomized phase II study of carboplatin and etoposide with or without the bcl-2 antisense oligonucleotide oblimersen for extensive-stage small-cell lung cancer: CALGB 30103. J Clin Oncol 26:870–876, 2008PubMedCrossRefGoogle Scholar
  55. 55.
    Marcucci G, Stock W, Dai G, et al: Phase I study of oblimersen sodium, an antisense to Bcl-2, in untreated older patients with acute myeloid leukemia: pharmacokinetics, pharmacodynamics, and clinical activity. J Clin Oncol 23:3404–3411, 2005PubMedCrossRefGoogle Scholar
  56. 56.
    Banker DE, Radich J, Becker A, et al: The t(8;21) translocation is not consistently associated with high Bcl-2 expression in de novo acute myeloid leukemias of adults. Clin Cancer Res 4:3051–3062, 1998PubMedGoogle Scholar
  57. 57.
    Moore J, Seiter K, Kolitz J, et al: A phase II study of Bcl-2 antisense (oblimersen sodium) combined with gemtuzumab ozogamicin in older patients with acute myeloid leukemia in first relapse. Leuk Res 30:777–783, 2006PubMedCrossRefGoogle Scholar
  58. 58.
    Larson RA, Boogaerts M, Estey E, et al: Antibody-targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin). Leukemia 16:1627–1636, 2002PubMedCrossRefGoogle Scholar
  59. 59.
    Marcucci G, Moser B, Blum W, et al: A phase III randomized trial of intensive induction and consolidation chemotherapy  ±  antisense oligonucleotide in untreated acute myeloid leukemia patients >60 years old. J Clin Oncol 25:360s, 2007 (suppl; abstr 7012)CrossRefGoogle Scholar
  60. 60.
    Badros AZ, Goloubeva O, Rapoport AP, et al: Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients. J Clin Oncol 23:4089–4099, 2005PubMedCrossRefGoogle Scholar
  61. 61.
    Chanan-Chan AA, Niesvizky R, Hohl RJ, et al: Randomized multicenter phase 3 trial of high-dose dexamethasone (dex) with or without oblimersen sodium (G3139; Bcl-2 antisense; Genasense) for patients with advanced multiple myeloma (MM). Blood 104:413a, 2004 (abstr 1477)Google Scholar
  62. 62.
    Data on file. Genta Incorporated. Berkeley Heights, NJGoogle Scholar
  63. 63.
    Chi K, Siu L, Hirte H, et al: A phase I study of OGX-011, a 2′-methoxyethyl phosphorothioate antisense to clusterin, in combination with docetaxel in patients with advanced cancer. Clin Cancer Res 14:833–839, 2007CrossRefGoogle Scholar
  64. 64.
    Chi K, Hotte S, Yu E, et al: A randomized phase II study of OGX-011 in combination with docetaxel and prednisone or docetaxel and prednisone alone in patients with metastatic hormone refractory prostate cancer (HRPC). J Clin Oncol 25:252s, 2007 (suppl; abstr 5069)CrossRefGoogle Scholar
  65. 65.
    Hau P, Jachimczak P, Schlingensiepen R, et al: Inhibition of TGF-β2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies. Oligonucleotides 17:201–212, 2007PubMedCrossRefGoogle Scholar
  66. 66.
    Schlingensiepen KH, Fischer-Blass B, Schmaus S, et al: Antisense therapeutics for tumor treatment: the TGF-beta2 inhibitor AP 12009 in clinical development against malignant tumors. Recent Results Cancer Res 177:137–150, 2008PubMedCrossRefGoogle Scholar
  67. 67.
    Bogdahn U, Oliushine VE, Parfenov VE, et al: Results of G004, a phase IIb study in recurrent glioblastoma patients with the TGF-β2 targeted compound AP 12009. J Clin Oncol 24:71s, 2006 (suppl; abstr 1553)Google Scholar
  68. 68.
    Nemunaitis J, Holmlund JT, Kraynak M, et al: Phase I evaluation of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C-alpha, in patients with advanced cancer. J Clin Oncol 17:3586–3595, 1999PubMedGoogle Scholar
  69. 69.
    Yuen AR, Halsey J, Fisher GA, et al: Phase I study of an antisense oligonucleotide to ­protein kinase C-alpha (ISIS 3521/CGP 64128A) in patients with cancer. Clin Cancer Res 5:3357–3363, 1999PubMedGoogle Scholar
  70. 70.
    Cripps MC, Figueredo AT, Oza AM, et al: Phase II randomized study of ISIS 3521 and ISIS 5132 in patients with locally advanced or metastatic colorectal cancer: a National Cancer Institute of Canada clinical trials group study. Clin Cancer Res 8:2188–2192, 2002PubMedGoogle Scholar
  71. 71.
    Tolcher AW, Reyno L, Venner PM, et al: A randomized phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 in patients with hormone-refractory prostate cancer. Clin Cancer Res 8:2530–2535, 2002PubMedGoogle Scholar
  72. 72.
    Villalona-Calero MA, Ritch P, Figueroa JA, et al: A phase I/II study of LY900003, an antisense inhibitor of protein kinase C-α, in combination with cisplatin and gemcitabine in patients with advanced non-small cell lung cancer. Clin Cancer Res 10:6086–6093, 2004PubMedCrossRefGoogle Scholar
  73. 73.
    Fire A, Xu S, Montgomery MK, et al: Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811, 1998PubMedCrossRefGoogle Scholar
  74. 74.
    Rana TM: Illuminating the silence: understanding the structure and function of small RNAs. Nat Rev Mol Cell Biol 8:23–36, 2007PubMedCrossRefGoogle Scholar
  75. 75.
    Elbashir SM, Harborth J, Lendeckel W, et al: Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498, 2001PubMedCrossRefGoogle Scholar
  76. 76.
    Rose SD, Kim DH, Amarzguioui M, et al: Functional polarity is introduced by Dicer processing of short substrate RNAs. Nucleic Acids Res 33:4140–4156, 2005PubMedCrossRefGoogle Scholar
  77. 77.
    Kim DH, Behlke MA, Rose SD, et al: Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy. Nat Biotechnol 23:222–226, 2005PubMedCrossRefGoogle Scholar
  78. 78.
    Siolas D, Lerner C, Burchard J, et al: Synthetic shRNAs as potent RNAi triggers. Nat Biotechnol 23:227–231, 2005PubMedCrossRefGoogle Scholar
  79. 79.
    Corey DR: Chemical modification: the key to clinical application of RNA interference? J Clin Invest 117:3615–3622, 2007PubMedCrossRefGoogle Scholar
  80. 80.
    Prakash TP, Allerson CR, Dande P, et al: Positional effect of chemical modifications on short interference RNA activity in mammalian cells. J Med Chem 48:4247–4253, 2005PubMedCrossRefGoogle Scholar
  81. 81.
    Fedorov Y, Anderson EM, Birmingham A, et al: Off-target effects by siRNA can induce toxic phenotype. RNA 12:1188–1196, 2006PubMedCrossRefGoogle Scholar
  82. 82.
    Morrissey DV, Lockridge JA, Shaw L, et al: Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol 23:1002–1007, 2005PubMedCrossRefGoogle Scholar
  83. 83.
    Chiu YL, Rana TM: siRNA function in RNAi: a chemical modification analysis. RNA 9:1034–1048, 2003PubMedCrossRefGoogle Scholar
  84. 84.
    Chen PY, Weinmann L, Gaidatzis D, et al: Strand-specific 5′-O-methylation of siRNA duplexes controls guide strand selection and targeting specificity. RNA 14:263–274, 2008PubMedCrossRefGoogle Scholar
  85. 85.
    Kubo T, Zhelev Z, Ohba H, et al: Modified 27-nt dsRNAs with dramatically enhanced stability in serum and long-term RNAi activity. Oligonucleotides 17:445–464, 2007PubMedCrossRefGoogle Scholar
  86. 86.
    Gaynor JW, Brazier J, Cosstick R: Synthesis of 3′-S-phosphorothiolate oligonucleotides for their potential use in RNA interference. Nucleosides Nucleotides Nucleic Acids 26:709–712, 2007PubMedCrossRefGoogle Scholar
  87. 87.
    Hall AH, Wan J, Shaughnessy EE, et al: RNA interference using boranophosphate siRNAs: structure-activity relationships. Nucleic Acids Res 32:5991–6000, 2004PubMedCrossRefGoogle Scholar
  88. 88.
    Hoshika S, Minakawa N, Matsuda A: RNA interference induced by siRNAs modified with 4′-thioribonucleosides. Nucleic Acids Symp Ser (Oxf) 49:77–78, 2005CrossRefGoogle Scholar
  89. 89.
    Mook OR, Baas F, de Wissel MB, et al: Evaluation of locked nucleic acid-modified small interfering RNA in vitro and in vivo. Mol Cancer Ther 6:833–843, 2007PubMedCrossRefGoogle Scholar
  90. 90.
    Elmén J, Thonberg H, Ljungberg K, et al: Locked nucleic acid (LNA) mediated improvements in siRNA stability and functionality. Nucleic Acids Res 33:439–447, 2005PubMedCrossRefGoogle Scholar
  91. 91.
    de Fougerolles A, Vornlocher HP, Maraganore J, et al: Interfering with disease: a progress report on siRNA-based therapeutics. Nat Rev Drug Discov 6:443–453, 2007PubMedCrossRefGoogle Scholar
  92. 92.
    Behlke MA: Progress towards in vivo use of siRNAs. Mol Ther 13:644–670, 2006PubMedCrossRefGoogle Scholar
  93. 93.
    Kim DH, Rossi JJ: Strategies for silencing human disease using RNA interference. Nat Rev Genet 8:173–184, 2007PubMedCrossRefGoogle Scholar
  94. 94.
    Bitko V, Musiyenko A, Shulyayeva O, et al: Inhibition of respiratory viruses by nasally administered siRNA. Nat Med 11:50–55, 2005PubMedCrossRefGoogle Scholar
  95. 95.
    Li BJ, Tang Q, Cheng D, et al: Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque. Nat Med 11:944–951, 2005PubMedGoogle Scholar
  96. 96.
    Palliser D, Chowdhury D, Wang QY, et al: An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection. Nature 439:89–94, 2006PubMedCrossRefGoogle Scholar
  97. 97.
    Jacque JM, Triques K, Stevenson M: Modulation of HIV-1 replication by RNA interference. Nature 418:435–438, 2002PubMedCrossRefGoogle Scholar
  98. 98.
    Coburn GA, Cullen BR: Potent and specific inhibition of human immunodeficiency virus type 1 replication by RNA interference. J Virol 76:9225–9231, 2002PubMedCrossRefGoogle Scholar
  99. 99.
    Rossi JJ, June CH, Kohn DB: Genetic therapies against HIV. Nat Biotechnol 25:1444–1454, 2007PubMedCrossRefGoogle Scholar
  100. 100.
    Kleinman ME, Yamada K, Takeda A, et al: Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452:591–597, 2008PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Oncology, Albert Einstein-Montefiore Cancer CenterMontefiore Medical CenterBronxUSA

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