Ebola future or investigational therapies

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Michael Maddaleni, B.S.

Overview

Although there is no effective human vaccine against Ebola currently available, there are promising results for antisense prevention therapies targeting the Ebola virus in monkey studies. Administration of an inhibitor of coagulation (rNAPc2) has demonstrated some benefit in monkey studies. There are non-conclusive results in human survivors from post-exposure vaccination, passive immunization with blood or serum or with recombinant human monoclonal antibodies.

Investigational Therapies

Treatment of Ebola virus disease

ZMapp

ZMapp is an experimental drug composed of 3 humanized monoclonal antibodies currently being investigated for the treatment of Ebola virus disease. The component monoclonal antibodies are recombinantly manufactured in a variety of tobacco (Nicotiana benthamiana). It has not yet been tested in humans for safety or effectiveness. Zmapp was studied in a preclinical study involving rhesus macaques exposed to the virus. The drug was successful in rescuing 100% (21/21) of the macaques when the treatment was initiated within 5 day of the Ebola exposure. High grade fever, and significant viraemia was present in many animals before intervention. Full recovery was also observed in animals with advanced disease with elevated liver enzymes, mucosal haemorrhages and generalized petechia. ZMapp was also found to be cross-reactive with the Guinean variant of Ebola. [1]

AVI-6002

AVI-6002 is an investigational drug consisting of positively charged phosphorodiamidate morpholino oligomers (PMOplus). AVI-6002 is a form of antisense therapy whereby a particular gene can be silenced by synthesizing a strand of nucleic acid (DNA, RNA or a chemical analogue) that will bind the messenger RNA (mRNA) produced by that gene. Pre-clinical studies demonstrated that AVI-6002 administered intravenously within 30-60 min of exposure to the virus protects approximately 60% of rhesus monkeys against the Zaire Ebola virus (ZEBOV).[2] A phase I trial that involved 30 healthy volunteers enrolled in six-dose escalation cohorts demonstrated good safety and tolerability of AVI-6002.[3]

TKM-Ebola

TKM-Ebola is a LNP-siRNA (lipid nanoparticle-small interfering RNA). Small interfering RNAs are a class of double-stranded RNA molecules that interfere with gene expression by causing breakdown of mRNA. TKM-Ebola is a combination of siRNAs targeting three of the seven proteins in Ebola virus: Zaire Ebola L polymerase, Zaire Ebola membrane-associated protein (VP24), and Zaire Ebola polymerase complex protein (VP35). A proof of concept study that included monkeys and macquees demonstrated approximately full protection from the virus when the drug was given 30 minutes post-exposure and repeat dosing was administered daily over the next 6 days.[4] In January 2014, a phase I clinical trial evaluating TKM-Ebola in healthy volunteers was announced. Although the study was initially put on hold due to significant flu-like symptoms, the FDA modified this to a partial clinical hold. This action enables the potential use of TKM-Ebola in individuals infected with Ebola virus.[5]

Prevention of Ebola virus diease

VSV-Ebola Vaccine

References

  1. Qiu X, Wong G, Audet J, Bello A, Fernando L, Alimonti JB; et al. (2014). "Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp". Nature. 514 (7520): 47–53. doi:10.1038/nature13777. PMID 25171469.
  2. Warren TK, Warfield KL, Wells J, Swenson DL, Donner KS, Van Tongeren SA; et al. (2010). "Advanced antisense therapies for postexposure protection against lethal filovirus infections". Nat Med. 16 (9): 991–4. doi:10.1038/nm.2202. PMID 20729866.
  3. Heald AE, Iversen PL, Saoud JB, Sazani P, Charleston JS, Axtelle T; et al. (2014). "Safety and Pharmacokinetic Profiles of Phosphorodiamidate Morpholino Oligomers with Activity against Ebola Virus and Marburg Virus: Results of Two Single Ascending Dose Studies". Antimicrob Agents Chemother. doi:10.1128/AAC.03442-14. PMID 25155593.
  4. Geisbert TW, Lee AC, Robbins M, Geisbert JB, Honko AN, Sood V; et al. (2010). "Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study". Lancet. 375 (9729): 1896–905. doi:10.1016/S0140-6736(10)60357-1. PMID 20511019.
  5. [| About Investigational TKM-Ebola Therapeutic. Tekmira Pharmaceuticals Corporation.]

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