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.

Public Health Relevance

Many glycoproteins which are potent antidotes, exhibit very important physiological functions but cannot be used as therapeutic treatments because they are difficult to deliver via injection due the high dose required The aim of this project is to administer butyrylcholinesterase via the pulmonary route in an aerosol inhalation device to that it deposits in the lung and forms a bioshield and detoxifies inhaled indecticides poisons in the lung and prevernts them from reaching the blood and the neuromuscular junctions where they can quickly cause severe toxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
2R44NS064608-04
Application #
8523566
Study Section
Special Emphasis Panel (ZRG1-ETTN-M (52))
Program Officer
Fertig, Stephanie
Project Start
2009-07-08
Project End
2015-08-31
Budget Start
2013-09-20
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$753,417
Indirect Cost
Name
Plantvax, Inc.
Department
Type
DUNS #
801465928
City
Rockville
State
MD
Country
United States
Zip Code
20850