Discovery and early development of AVI-7537 and AVI-7288 for the treatment of Ebola virus and Marburg virus infections

Viruses

Volumn 4, Issue 11, 2012, Pages 2806-2830

  Iversen, Patrick L ^a   Warren, Travis K ^b   Wells, Jay B ^b   Garza, Nicole L ^b   Mourich, Dan V ^a   Welch, Lisa S ^b   Panchal, Rekha G ^b   Bavari, Sina ^b  

^a AVI BIOPHARMA INC   (United States)

^b UNITED STATES ARMY MEDICAL RESEARCH INSTITUTE OF INFECTIOUS DISEASES   (United States)

Author keywords

Antiviral; Ebola; Marburg; Phosphorodiamidate morpholino oligomer; PMOplus; Therapeutic

Indexed keywords

AVI 7288; AVI 7537; MORPHOLINO OLIGONUCLEOTIDE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DRUG STRUCTURE; DRUG SYNTHESIS; EBOLA VIRUS; EBOLA VIRUS INFECTION; FILOVIRUS INFECTION; GUINEA PIG; MARBURG HEMORRHAGIC FEVER; MARBURG VIRUS; MOUSE; NONHUMAN; NP GENE; VIRUS GENE; VIRUS ISOLATION; VIRUS TRANSCRIPTION; VP24 GENE;

ANIMALS; ANTIVIRAL AGENTS; BASE SEQUENCE; EBOLAVIRUS; GENES, VIRAL; GUINEA PIGS; HEMORRHAGIC FEVER, EBOLA; MARBURG VIRUS DISEASE; MARBURGVIRUS; MICE; MORPHOLINOS; OLIGODEOXYRIBONUCLEOTIDES, ANTISENSE; PRIMATES; PROTEIN BIOSYNTHESIS; RNA, MESSENGER; RNA, VIRAL;

CAVIA; EBOLA VIRUS; LAKE VICTORIA MARBURGVIRUS; MARBURGVIRUS;

EID: 84870580050     PISSN: 19994915     EISSN: None     Source Type: Journal    
DOI: 10.3390/v4112806     Document Type: Article

References (55)

1. Kortepeter, M.G.; Bausch, D.G.; Bray, M. Basic clinical and laboratory features of filoviral hemorrhagic fever. J. Infect. Dis. Suppl. 2011, 3, S810-816.
2. Shurtleff, A.C.; Warren, T.K.; Bavari, S. Nonhuman primates as models for the discovery and development of ebolavirus therapeutics. Expert Opin. Drug Devel. 2011, 6, 233-250.
3. Jahrling, P.B.; Geisbert, J.; Swearengen, J.R.; Jaax, G.P.; Lewis, T.; Huggins, J.W.; Schmidt, J.J.; LeDuc, J.W.; Peters, C.J. Passive immunization of Ebola virus-infected cynomolgus monkeys with immunoglobin fom hyerimmune horses. Arch. Virol. Suppl. 1996, 11, 135-140.
4. Zeitlin, L.; Pettitt, J.; Scully, C.; Bohorova, N.; Kim, D.; Pauly, M.; Hiatt, A.; Ngo, L.; Steinkellner, H.; Whaley, K.J.; Olinger, G.G. Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectant. Proc. Natl. Acad. Sci. USA 2011, 108, 20690-20694.
5. Marzi, A.; Yoshida, R.; Miyamoto, H.; Ishijima, M.; Suzuki, Y.; Higuchi, M.; Matsuyama, Y.; Igarashi, M.; Nakayama, E.; Kuroda, M.; Saijo, M.; Feldman, F.; Brining, D.; Feldman, H.; Takada, A. Protective efficacy of neutralizing monoclonal antibodies in a nonhuman primate model of Ebola hemorrhagic fever. PLoS ONE 2012, 7:e36192.
6. Bradfute, S.B.; Warfield, K.L.; Bavari, S. Functional CD8+ T cell responses in lethal Ebola Virus infection. J Immunol. 2008, 180, 4058-4066.
7. Martin, J.E.; Sullivan, N.J.; Enama, M.E.; Gordon, I.J.; Roeder, M.; Koup, R.A.; Bailer, R.T.; Chakrabarti, B.K.; Bailey, M.A.; Gomez, P.L.; Andrews, C.A.; Moodie, A.; Gu, L.; Stein, J.A.; Nabel, G.J.; Graham, B.S. A DNA vaccine for Ebola Virus is safe and immunogenic in a phase I clinical trial. Clin. Vac. Immunol. 2006, 13, 1267-1277.
8. Limberis, M.P.; Bell, C.L.; Heath, J.; Wilson, J.M. Activation of transgene-specific T cells following lentivirus-mediated gene delivery to mouse lung. Mol. Ther. 2010, 18, 143-150.
9. Sullivan, N.J.; Geisbert, T.W.; Geisbert, J.B.; Shedlock, D.J.; Xu, L.; Lamoreaux, L.; Custers, J.H.H.V.; Popernack, P.M.; Yang, Z.Y.; Pau, M.G.; Roeder, M.; Koup, R.A.; Goudsmit, J.; Jahrling, P.B.; Nabel, G.J. Immune protection of nonhuman primates against Ebola Virus with single low-dose adenovirus vectors encoding modified GPs. PLoS ONE 2006, 3:e177.
10. Hensley, L.E.; Stevens, E.L.; Yan, S.B.; Geisbert, J.B.; Macias, W.L.; Larsen, T.; Daddario-DiCaprio, K.M.; Cassell, G.H.; Jahrling, P.B.; Geisbert, T.W. Recombinant human activated protein C for the postexposure treatment of Ebola hemorrhagic fever. J. Infect. Dis. Suppl. 2007, 15, S390-399.
11. Geisbert, T.W.; Lee, A.C.; Robbins, M.; Geisbert, J.B.; Honko, A.N.; Sood, V.; de Jong, S.; Tavakoli, I.; Judge, A.; Hensley, L.E.; Maclachlan, I. Postexposure protection of non-human primates against lethal Ebola virus-challenge with RNA interference: a proof-of-concept study. Lancet 2010, 29, 1896-1905.
12. Summerton, J.; Weller, D. Morpholino Antisense Oligomers: Design, Preparation and Propoerties. Antisense Nucleic A. 1997, 7, 187-195.
13. Iversen, P. Phosphorodiamidate morpholino oligomers: Favorable properties for sequence-specific gene inactivation. Curr. Opin. Mol. Ther. 2001, 3, 235-238.
14. Hudziak, R.M.; Barofsky, E.; Barofsky, D.F.; Weller, D.L.; Huang, S.B.; Weller, D.D. Resistance of Morpholino Phosphorodiamidate Oligomers to Enzymatic Degradation. Antisense Nucleic A. 1996, 6:267-272.
15. Hudziak, R.M.; Summerton, J.; Weller, D.L.; Iversen, P.L. Antiproliferative Effects of Steric Blocking Phosphorodiamidate Morpholino Antisense Agents Directed Against c-myc. Antisense Nucleic A. 2000, 10, 163-176.
16. Kipshidze, N.N.; Kim, H-S; Iversen, P.L.; Yazdi, H.A.; Bhargava, B.; Mehran, R.; Haundenschild, C.; Dangas, G.; Stone, G.W.; Roubin, G.S.; Leon, M.B.; Moses, J.W. Intramural Delivery of Advanced Antisense Oligonucleotides with Infiltrator Cathetor Inhibits c-myc Expression and Intimal Hyperplasia in the Porcine. J. Am. Col. Cardiol. 2002, 39, 1686-1691.
17. Ricker, J.L.; Mata, J.E.; Iversen, P. L; Gattone, V.H. c-myc Antisense Oligonucleotide Treatment Ameliorates Murine Infantile Polycystic Kidney Disease. Kidney Int. 2002, 61, S125-S131.
18. Devi, G.R.; Oldencamp, J.R.; London, C.A.; Iversen, P.L. Inhibition of Human Chorionic Gonadotropin beta-Subunit Modulates the Mitogenic Effect of c-myc in Human Prostate Cancer Cells. The Prostate 2002, 53, 200-210.
19. Knapp, D.C.; Mata, J.E.; Reddy, M.T.; Devi, G.R.; Iversen, P.L. Resistance to Chemotherapeutic Drugs Overcome by c-Myc Inhibition in Lewis Lung Carcinoma Model. Anti-Cancer Drug. 2003, 14, 39-47.
20. Iversen, P.L.; Arora, V.; Acker, A.J.; Mason, D.H.; Devi, G.R. Efficacy of Antisense Morpholino Oligomer Targeted to c-myc in Prostate Cancer Xenograft Model and a Phase I Safety Study in Humans. Clin. Cancer Res. 2003, 9, 1-10.
21. Arora, V.; Cate, M.; Ghosh, C.; Iversen, P.L. Phosphorodiamidate Morpholino Oligomers Inhibit Expression of Human Cytochrome P450 3A4 and Alter Selected Drug Metabolism. Drug Metab. Dispos. 2002a, 30, 1-6.
22. Arora, V.; Hannah, T.L.; Iversen, P.L.; Brand, R.M. Transdermal Use of Phosphorrdiamidate Morpholino Oligomer AVI-4472 Inhibits Cytochrome P450 3A2 Activity in Male Rats. Pharm. Res. 2002b, 19, 1465-1470.
23. Stein, D.A.; Skilling, D.E.; Iversen, P.L.; Smith, A.W. Inhibition of Vesivirus Infetions in Mammalian Tissue Culture with Antisense Morpholino Oligomers. Antisense Nucleic A. 2001, 11, 317-325.
24. Smith, A.W.; Iversen, P.L.; O'Hanley, P; Christensen, JR; Stein, D.A.; Skilling, D.E.; Weaver, S.S.; Longley, K.; Stone, M.; Poet, S.E.; Matson, D.O. Virus Specific Antiviral Therapy for Controlling Severe and Fatal Outbreaks of Feline Calicivirus Infection. Am. J. Vet. Res. 2008, 69, 23-32.
25. Warfield, K.L.; Swenson, D.L.; Olinger, G.G.; Nichols, D.K.; Pratt, W.D.; Blouch, R.; Stein, D.A.; Aman, M.J.; Iversen, P.L.; Bavari, S. Gene-Specific Countermeasures against Ebola Virus Based on Antisense Phosphorodiamidate Morpholino Oligomers. PLoS Pathog. 2006, 2, 1-9.
26. Stein, D.; Foster, E.; Huang, S.B.; Weller, D.; Summerton, J. A specificity comparison of four antisense types: Morpholino, 2'-O-methyl RNA, DNA, and phosphorothioate DNA. Antisense Nucleic A. 1997, 7, 151-157.
27. Fall, A.M.; Johnsen, R.; Honeyman, K.; Iversen, P.; Fletcher, S.; Wilton, S.D. Induction of revertant fibres in the mdx mouse using antisense oligonucletoides. Genet. Vaccines Ther. 2006, 4, 3-15.
28. Adams, A.M.; Harding, P.L.; Iversen, P.L.; Coleman, C.; Fletcher, S.; Wilton, S.D. Antisense oligonucleotide induced exon skipping and the dystrophin gene transcript: cocktails and chemistries. BMC Mol. Biol. 2007, 8, 57-65.
29. Kinali, M.; Arechavala-Gomeza, V.; Feng, L.; Cirak, S.; Hunt, D.; Adkin, C.; Guglieri, M.; Ashton, E.; Abbs, S.; Nihoyannopoulos, P.; Garralda, M.E.; Rutherford, M.; Mcculley, C.; Popplewell, L.; Graham, I.R.; Dickson, G.; Wood, M.J.; Wells, D.J.; Wilton, S.D.; Kole, R. Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol. 2009. 8, 918-928.
30. Cirak, S.; Arechavala-Gomeza, V.; Guglieri, M.; Feng, L.; Torelli, S.; Anthony, K.; Abbs, S.; Garralda, M.E.; Bourke, J.; Wells, D.J.; Dickson, G.; Wood, M.J.; Wilton, S.D.; Straub, V.; Kole, R.; Shrewsbury, S.B.; Sewry, C.; Morgan, J.E.; Bushby, K.; Muntoni, F. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet 2011, 378, 595-605.
31. Moulton, H.M.; Hase, H.C.; Smith, K.H.; Iversen, P.L. HIV Tat Peptide Enhances Cellular Delivery of Antisense Morpholino Oligomers. Antisense Nucleic A. 2003, 13, 32-37
32. Moulton, H.M.; Nelson, M.H.; Hatlevig, S.A.; Reddy, M.T.; Iversen, P.L. Cellular Uptake of Antisense Morpholino Oligomers Conjugated to Arginine-Rich Peptides BioConjugate Chem. 2004, 15, 290-299.
33. Abes, S.; Moulton, H.M.; Clair, P.; Prevot, P.; Youngblood, D.S.; Wu, R.P.; Iversen, P.L.; Lebleu, B. Vectorization of morpholino oligomers by the (R-Ahx-R)(4) peptide allows efficient splicing correction in the absence of endosomolytic agents. J. Control. Release 2006, 116, 304-345.
34. Youngblood, D.S.; Hatlevig, S.A.; Hassinger, J.N.; Iversen, P.L.; Moulton, H.M. Stability of Cell-Penetrating Peptide-Morpholino Oligomer Conjugates in Human Serum and in Cells. Bioconjugate Chem. 2006, 18, 50-60.
35. Wu, R.P.; Youngblood, D.S.; Hassinger, J.N.; Lovejoy, C.E.; Nelson, M.H.; Iversen, P.L.; Moulton, H.M. Cell-Penetrating Peptides as Transporters for Morpholino Oligomers: Effects of Amino Acid Composition on Intracellular Delivery and Cytotoxicity. Nucleic Acids Res. 2007, 35, 5182-5191.
36. Marshall, N.B.; Oda, S.K.; London, C.A.; Moulton, H.M.; Iversen, P.L.; Kerkvliet, N.I.; Mourich, D.V. Arginine-rich cell penetrating peptides facilitate delivery of antisense oligomers into murine leukocytesand alter pre-mRNA splicing. J. Immunology Methods 2007, 325, 114-126.
37. Lebleu, B.; Moulton, H.M.; Abes, R.; Ivanova, G.D.; Abes, S.; Stein, D.A.; Iversen, P.L.; Arzumanov, A.A.; Gait, M.J. Cell penetrating peptide conjugates of steric block oligonucleotides. Adv. Drug Deliv. Rev. 2008, 77, 95-107
38. Geller, B.L.; Deere, J.D.; Stein, D.A.; Kroeker, A.D.; Moulton, H.M.; Iversen, P.L. Inhibition of Gene Expression in Escherichia coli by Antisense Phosphorodiamidate Morpholino Oligomers. Antimicrob. Agents Ch. 2003, 47, 3233-3239
39. Deere, J.; Iversen, P.; Geller, B.L. Antisense phosphorodiamidate morpholino oligomer length and target position effects on gene-specific inhibition in Escherichia coli. Antimicrob. Agents Ch. 2005, 49, 249-255.
40. Geller, B.L.; Deere, J.; Tilley, L.; Iversen, P.L. Antisense phosphorodiamidate morpholino oligomer inhibits viability of Escherichia coli in pure culture and in mouse peritonitis. J. Antimicrob. Chemoth. 2005, 10, 1093
41. Tilley, L. D; Mellbye, B.L.; Puckett, S.E.; Iversen, P.L.; Geller, B.L. Antisense peptide-phosphorodiamidate morpholino oligmer conjugate: dose-response in mice infected with Escherichia coli. J. Antimicrob. Chemoth. 2007, 59, 66-73.
42. Mellbye, B.L.; Puckett, S.E.; Tilley, L.D.; Iversen, P.L.; Geller, B.L. Variations in amino acid composition of antisense peptide-phosphorodiamidate Morpholino oligomer affect potency in vitro and in vivo. Antimicrob. Agents Chemother. 2009, 53, 525-530
43. Greenberg, D.E.; Marshall-Batty, K.R.; Brinster, L.R.; Zarember, K.A.; Shaw, P.A.; Mellbye, B.L.; Iversen, P.L.; Holland, S.M.; Geller, B.L. Antisense phosphorodiamidate morpholino oligomers targeted to an essential gene inhibit Burkholderia cepacia complex. J. Infect. Dis. 2010, 201, 1822-1830.
44. Tilley, L.D.; Hine, O.S.; Kellogg, J.A.; Hassinger, J.N.; Weller, D.D.; Iversen, P.L.; Geller, B.L. Gene-Specific Effects of Antisense Phosphorodiamidate Morpholino Oligomer-Peptide Conjugates on Escherichia coli and Salmonella enterica Serovar Typhimurium in Pure Culture and in Tissue Culture. Antimicrob. Agents Ch. 2006, 50, 2789-2796.
45. Mitev, G.M.; Mellbye, B.L.; Iversen, P.L.; Geller, B.L. Inhibition of Intracellular Growth of Salmonella enterica serovar typhimurium in Tissue Culture by Antisense Peptide-Phosphorodiamidate Morpholino Oligomer. Antimicrob. Agents Ch. 2009, 53, 3700-3704.
46. Enterlein, S.; Warfield, K.L.; Swenson, D.L.; Stein, D.A.; Smith, J.L.; Gamble, C.S.; Kroeker, A.D.; Iversen, P.L.; Bavari, S.; Muhlberger, K. VP35 Knockdown Inhibits Ebola Virus Amplification and Protects against Lethal Infection in Mice. Antimicr. Agents Ch. 2006, 50, 984-993.
47. Swenson, D.L.; Warfield, K.L.; Warren, T.K.; Moulton, H.; Blouch, R.; Ruthel, G.; Iversen, P.L.; Bavari, S. Chemical modifications to phosphorodiamidate Morpholino oligomer antisense molecules targeting VP24 modify their efficacy against Ebola virus infection. Antimicrob Agents Ch. 2009, 53, 2089-2099.
48. Yuan, J.; Stein, D.A.; Lim, T.; Qiu, D.; Coughlin, S.; Liu, Z.; Wang, Y.; Blouch, R.; Moulton, H.M.; Iversen, P.L.; Yang, D. Inhibition of coxsackievirus b3 in cell cultures and in mice by Peptide-conjugated morpholino oligomers targeting the internal ribosomal entry site. J. Virol. 2006, 80, 11510-11519.
49. Gabriel, G.; Nordman, A.; Stein, D.A.; Iversen, P.L.; Klend, H.-D. Morpholino Oligomers Targeting the PB1 and NP Genes Enhance Survival of Mice Infected with highly Pathogenic Influenza A H7N7 Virus. J. Gen. Virol. 2008, 89, 939-948.
50. Lupfer, C.; Stein, D.A.; Mourich, D.V.; Tepper, S.E.; Iversen, P.L.; Pastey, M. Inhibition of influenza A H3N8 virus infections in mice by morpholino oligomers. Arch. Virol. 2008, 153, 929-937.
51. Paessler, S.; Rijnbrand, R.; Stein, D.A.; Ni, H.; Yun, N.E.; Dziuba, N.; Borisevich, V.; Seregin, A.; Ma, Y.; Blouch, R.; Iversen, P.L.; Zacks, M.A. Inhibition of alphavirus infection in cell culture and in mice with antisense morpholino oliogmers. Virology 2008, 5, 357-370.
52. Stone, J.; Stein, D.A.; Rijnbrand, R.; Iversen, P.L.; Andino, R. Inhibition of multiple species of picornavirus using a morpholino oligomer targeting highly conserved IRES sequence. Antimicrob Agents Ch. 2008, 52, 1970-1981.
53. Warren, T.K.; Warfield, K.L.; Wells, J.; Swenson, D.L.; Donner, K.S.; Van Tongeren, S.A.; Garza, N.L.; Dong, L.; Mourich, D.V.; Crumley, S.; Nichols, D.K.; Iversen, P.L.; Bavari, S. Advanced antisense therapies for postexposure protection against lethal filovirus infections. Nat. Med. 2010, 991-994.
54. Hudziak, R.M.; Summerton, J.; Weller, D.P.; Iversen, P.L. Antiproliferative Effects of Steric Blocking Phosphorodiamidate Morpholino Antisense Agents Directed Against c-myc. Antisense Nucleic A. 2000, 10, 163-176.
55. Stein, D.A.; Huang, C.Y.H.; Silengo, S.; Amantana, A.; Crumley, S.; Blouch, R.E.; Iversen, P.L.; Kinney, R.M. Treatment of AG129 mice with antisense morpholino oligomers increases survival time following challenge with dengue 2 virus. J. Antimicrob. Ch. 2008, 62, 555-565.