Research ArticleGene Therapy

Gene therapy delivering a paraoxonase 1 variant offers long-term prophylactic protection against nerve agents in mice

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Science Translational Medicine  22 Jan 2020:
Vol. 12, Issue 527, eaay0356
DOI: 10.1126/scitranslmed.aay0356

Long-lasting protection

Nerve agents are the most toxic and lethal warfare chemical compounds. The toxic effect is due to inhibition of the acetylcholinesterase enzymes. Current antidotes prevent death but are ineffective against complications including brain damage and behavioral impairments. To prevent these deleterious consequences, now, Betapudi et al. developed a prophylactic gene therapy delivering the gene coding for a variant of the nerve agent scavenger paraoxonase 1 (PON1). When injected systemically in mice, the treatment exerted long-lasting protection against different types of nerve agents without signs of toxicity. The results suggest that gene therapy might be a viable option as prophylactic treatment in subjects at risk of exposure to nerve agents such as military personnel in war zones.


Chemical warfare nerve agents are organophosphorus chemical compounds that induce cholinergic crisis, leaving little or no time for medical intervention to prevent death. The current chemical treatment regimen may prevent death but does not prevent postexposure complications such as brain damage and permanent behavioral abnormalities. In the present study, we have demonstrated an adeno-associated virus 8 (AAV8)–mediated paraoxonase 1 variant IF-11 (PON1-IF11) gene therapy that offers asymptomatic prophylactic protection to mice against multiple lethal doses of G-type chemical warfare nerve agents, namely, tabun, sarin, cyclosarin, and soman, for up to 5 months in mice. A single injection of liver-specific adeno-associated viral particles loaded with PON1-IF11 gene resulted in expression and secretion of recombinant PON1-IF11 in milligram quantities, which has the catalytic power to break down G-type chemical warfare nerve agents into biologically inactive products in vitro and in vivo in rodents. Mice containing milligram concentrations of recombinant PON1-IF11 in their blood displayed no clinical signs of toxicity, as judged by their hematological parameters and serum chemistry profiles. Our study unfolds avenues to develop a one-time application of gene therapy to express a near-natural and circulating therapeutic PON1-IF11 protein that can potentially protect humans against G-type chemical warfare nerve agents for several weeks to months.

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