Gene and Protein Therapy for Poisoning by Organophosphorus Agents

Abstract : The goal of this work is to find new treatment strategies for poisoning by nerve agents. A gene therapy protocol capable of delivering human acetylcholinesterase into dividing as well as nondividing cells is being developed, using adeno-associated virus to transfer the gene. The idea that an organophosphate hydrolase enzyme in the right location will provide protection against organophosphorus agents is being tested in a mouse. A gene targeted mouse that has the human butyrylcholinesterase Gll7H gene in place of the acetyicholinesterase gene is being made. The Gll7H enzyme is of special interest because it not only hydrolyzes acetylcholine but also hydrolyzes organophosphorus toxicants. Another type of mouse, one that contains random insertions of the human butyrylcholinesterase Gll7H gene, has been made. This transgenic mouse contains multiple copies of the human gene in its chromosomes. The plan is to make a stable transgenic mouse line and then test it for resistance to the toxicity of organophosphorus agents.