Protection against Inhaled Sarin Nerve Agent Toxicity by Pretreatment with Aerosolized Recombinant Butyrylcholinesterase in Macaques
Abstract
Sarin use in Syria highlights the urgent need for a nerve agent antidote. Directly in line with HDTRA1-09-14-FRCWMD-BAA (TA3) aims, PlantVax is developing an aerosolized recombinant human butyrylcholinesterase (aer-rHuBChE) pretreatment to prevent neurotoxicity associated with inhaled nerve agent and pesticide OP exposure. Although the efficacy of plasma-derived BChE prophylaxis in animals against multiple LD50s of nerve agents is well established, limited availability and high cost of the large doses required for protection, have led to a focus on a rBChE countermeasure. Due to poor plasma retention following parenteral (i.v., i.m., s.c.) delivery, rBChE forms require engineering or PEG-ylation resulting in both variable pharmacokinetics and substantially increased cost. PlantVax’s alternate approach is to deliver rBChE as an aerosol, taking advantage of the fact that rBChE molecules are too large to exit the lung and instead form a “pulmonary bioshield” that can scavenge incoming (inhaled) OPs in situ preventing their entry into the systemic circulation, inhibition of cholinesterases in neuromuscular junctions and neurotoxicity. PlantVax’s prior protection studies in macaques using aer-rBChE have successfully demonstrated that aer-rHuBChE (~9/mg/kg) can totally prevent red blood cell acetylcholinesterase (RBC-AChE) and plasma BChE inhibition following exposure with 15ug/kg of aerosolized paraoxon (a potent pesticide) given 1- 40 hours later; compared with 63% inhibition in untreated animals. In addition, aer-rHuBChE delivered using a nebulizer prevents tremours in macaques following high doses of inhaled paraoxon. In this Phase II proposal, the ability of 14mg/kg of aer-rHuBChE to protect against a lethal dose of inhaled sarin administered from 24 to 48hr following pretreatment will be assessed
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 13, 2016
- Source ID
- HDTRA11510026
Entities
People
- Yvonne Rosenberg
Organizations
- Defense Threat Reduction Agency
- Plantvax (United States)