Somatic Gene Therapy in the Prevention of Toxic Effects of Organophosphate Agents

Abstract

Medical intervention in poisoning by organophosphate toxic agents (OPA) using atropine sulfate, 2-pyridinaldoxymethyl chloride (2-PAM), diazepam and other similar drugs can prevent the fatal outcome of poisoning. These drugs do not protect in case of sudden chemical attack and against post-exposure complications associated with permanent brain damage. The U.S. Department of Defense is funding research that can significantly simplify the protection of military personnel from OPA damage in the future. Their essence is in the use of gene therapy technologies, which allow experimental animals to produce their own proteins that destroy OPA and provide them with protection for several months. The aim of the work is to identify the achieved level of knowledge in the research using gene therapy technologies to create living objects resistant to OPA. The research method is analytical. The source base of the research are publications in scientific journals and descriptions of patents. Discussion of the results. As an enzyme that breaks down OPA in such experiments, genetically modified paraoxanase 1 (PON1) showed the greatest efficiency. PON1 hydrolyzes G-type OPAs, paraoxone, chlorpyrifosoxone, diazoxone and several other organophosphates. Adenoassociated virus vectors (AAV8, etc.) were used to introduce the gene encoding PON1 into the animal's body. A single injection of AAV8 carrying the recombinant PON1-IF11 gene (AAV8-PON1-IF11) resulted in high expression and secretion of the recombinant PON1-IF11 protein into the bloodstream and provided asymptomatic protection against multiple lethal doses of G-type OPA for at least 5 months. These studies are still in their early stage. An analysis of the affiliation of the authors of publications and patents showed a high involvement of the U.S. military department and its cooperating organizations (DTRA, etc.) in such research. Conclusion. Given the fascination in the West with the ideas of human modification using gene therapy methods, this direction will be intensively developed for military purposes. At the same time, the idea of pre-created resistance to OPA is in demand by the widespread use of organophosphates in agriculture. The author believes that it would be safer to use allogeneic mesenchymal stem cells transfected with genetically modified PON1 variants with enhanced enzyme activity. This resistance to OP agents can be health protective and lifesaving in soldiers in real combat when the enemy uses these agents. However, this approach must be based on a strong experimental background. The door is open, the technologies are available.