Efficacy and Safety of an Aerosolized Recombinant Butyrylcholinesterase Pretreatm

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 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 andquot pulmomary bioshieldandquot 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 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 andquot pulmonary bioshieldandquot 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 andquot bioshieldandquot 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