Bioscavengers to protect against chemical warfare nerve agents: safety of adenovirus‐driven expression of butyrylcholinesterase in macaques

Abstract

To date, no pretreatment against chemical warfare nerve agents offers better protection than endogenous esterases. These bioscavengers are capable of sequestering nerve agents and protecting acetylcholinesterase from inactivation, thereby preventing the toxic and lethal effects of the nerve agents. The current leading bioscavenger (butyrylcholinesterase, BChE) is purified from human serum and is quite expensive. Additionally, the enzyme is only capable of binding nerve agents stoichiometrically; thus, large amounts of human BChE are required to protect against large doses of nerve agent. A novel approach is to utilize an adenovirus to produce higher levels of in vivo expression of an esterase, thereby providing prolonged protection without the need to purify large quantities of the bioscavenger. Thus, cynomolgus macaques were injected with an adenovirus designed to increase BChE systemically. The safety and pharmacokinetic profile of the virus infection is currently ongoing. To assess efficacy of this pretreatment, monkeys will perform the temporal response differentiation task before and after infection with the virus and will be challenged with an otherwise lethal dose of nerve agent to demonstrate neurobehavioral protection. This research is supported by the Defense Threat Reduction Agency – Joint Science and Technology Office, Medical S&T Division.