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

Area of Science:

• Biochemistry
• Gene Therapy
• Toxicology

Background:

• Chemical warfare nerve agents are organophosphorus compounds causing rapid, life-threatening cholinergic crisis.
• Current treatments prevent death but not long-term neurological and behavioral complications.
• There is a critical need for effective prophylactic countermeasures against nerve agent exposure.

Purpose of the Study:

• To evaluate the efficacy of adeno-associated virus 8 (AAV8)-mediated paraoxonase 1 variant IF-11 (PON1-IF11) gene therapy as a prophylactic treatment against G-type chemical warfare nerve agents.
• To assess the duration of protection and potential toxicity of the gene therapy in a rodent model.

Main Methods:

• Administration of AAV8 vectors carrying the PON1-IF11 gene via a single injection.
• Assessment of recombinant PON1-IF11 expression and secretion in vivo.
• Testing of protection against multiple lethal doses of G-type nerve agents (tabun, sarin, cyclosarin, soman).
• Evaluation of hematological and serum chemistry profiles for toxicity.

Main Results:

• A single gene therapy injection resulted in milligram quantities of circulating PON1-IF11 protein.
• The recombinant PON1-IF11 effectively degraded G-type nerve agents in vitro and in vivo.
• Mice showed asymptomatic protection against multiple lethal nerve agent doses for up to 5 months.
• No clinical signs of toxicity were observed in treated mice.

Conclusions:

• AAV8-mediated PON1-IF11 gene therapy offers effective, long-lasting prophylactic protection against multiple G-type nerve agents.
• This one-time gene therapy approach yields a circulating therapeutic protein with potential for human application.
• The study presents a promising strategy for developing durable countermeasures against chemical warfare nerve agents.