Efficacy and Safety of an Aerosolized Recombinant Butyrylcholinesterase Pretreatm

Summary

Principal Investigator: YVONNE J ROSENBERG
Abstract: DESCRIPTION (provided by applicant): Organophosphorus (OPs) compound are potent neurotoxic chemicals that are widely used in medicine, industry and agriculture;most notably as insecticides. The neurotoxicity which is primarily a result of AChE inhibition, may take the form of cholinergic crisis and death as a consequence of acute exposure or psychiatric symptoms and may lead to delayed neuropathy following chronic exposure. Usually, treatment of insecticide poisoning consists of supportive care and specific therapy e.g. atropine and oximes, which often fail to prevent morbidity or death. Currently, recombinant (r) BChE is a leading pre-exposure treatment candidate for OP toxicity due to its potent bioscavenging ability but because of its 1:1 stoichiometry with OP, large doses will be required and without post-transitional modification, rBChRE exhibits poor circulatory stability when administered im, iv or sc. To overcome the potential challenges associated with parenteral delivery, PlantVax has taken advantage of the large size of the BChE molecules and has developed an innovative delivery approach using an aerosolized (aer) form of rBChE. Thus BChE delivered as an aerosol coats the airways of the lungs forming a "pulmomary bioshield" that can scavenge incoming (inhaled) OPs in situ: preventing both their entry into the systemic circulation and their inhibition of AChE on RBC and in neuromuscular junctions. This route of administration is highly relevant since inhalation of vapors and particles is the predominant form of exposure to insecticides and G-type nerve agents and serves as a major means of intoxication because of rapid accesses of the OP to the blood. In Phase I Phase I feasibility studies, aer-rBChE was shown to protect against paraoxon (Px) toxicity in mice while in Phase II, unmodified aer-rMaBChE and aer-rHuBChE were shown to almost totally protect macaques even when aer-Px exposure occurred 40 hr following pretreatment. Since, in these experiments, aer-rBChE and aer-Px were delivered using a microsprayer, the proposed Phase IIB studies will extend these findings and will perform efficacy and early non-GLP safety testing using aerosl inhalation (nebulizer) devices to directly assess whether an inhaled "pulmonary bioshield" is efficacious in preventing OP toxicity and whether it is safe. These studies represent the first time BChE has been shown to protect against an insecticide and bode well for an aer-rHuBChE pre-exposure treatment against inhaled OPs in humans even when repurposed for use against nerve agents and inhaled cocaine toxicity.
Funding Period: 2009-07-08 - 2015-08-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  2. Center for Narcolepsy and Related Disorders (P50)
    Emmanuel J Mignot; Fiscal Year: 2013
    ..We also want to understand why the immune system destroys hypocretin neurons in narcolepsy and to prevent/cure it. ..
  3. Center for Children's Environmental Health Research
    Brenda Eskenazi; Fiscal Year: 2013
    ..Our ultimate goal is to translate research findings into sustainable strategies to reduce pesticide and other exposures to children, thus reducing the incidence of environmentally-related disease. ..
  4. Southeast Regional Centers of Excellence for Biodefense &Emerging Infectious Di
    Philip Frederick Sparling; Fiscal Year: 2013
    ..SERCEB brings new investigators to the biodefense effort through a combination of educational programs, support of innovative new projects, and the synergistic interactions among its world-class investigators. ..
  5. LIAI Epitope Validation Center: Characterization of Allergen specific T Cells
    ALESSANDRO D SETTE; Fiscal Year: 2013
    ..abstract_text> ..
  6. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
    ..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
  7. BIOMARKERS OF EXPOSURE TO HAZARDOUS SUBSTANCES
    Bruce D Hammock; Fiscal Year: 2013
    ..abstract_text> ..
  8. Superfund Metal Mixtures, Biomarkers and Neurodevelopment
    David C Bellinger; Fiscal Year: 2013
    ..Aim 4- To promote rapid dissemination of significant research findings;and Aim 5- Compliance- To ensure compliance with NIH requirements for data and resource-sharing and the human and animal institutional review board requirements ..
  9. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  10. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
    ..The program will be overseen and coordinated by an Administration core (A). ..
  11. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  12. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
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  13. Phase I clinical trial of an immunoadhesin antitoxin for anthrax
    KEITH WYCOFF; Fiscal Year: 2013
    ....