MMSL 2018, 87(88):41

PARAOXONASE 1 VARIANT I-F11 GENE THERAPY USING ADENO-ASSOCIATED VIRUS8 (AAV8) OFFERS LONG-TERM PROTECTION AGAINST G-TYPE CHEMICAL WARFARE NERVE AGENTSMeeting abstracts

Venkaiah Betapudi, Deborah M. Doctor, Nageswararao Chilukuri
Agent Mitigation, Neuroscience Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD, 21010 USA

The paraoxonase 1 variant I-F11 affords asymptomatic protection against the lethal effects of G-type chemical warfare nerve agents (CWNA). Here, we tested whether adeno-associated virus8 (AAV8) is able to deliver I-F11 for extended periods of time and at levels affording asymptomatic protection against 2-5LD50 doses of G-type CWNA in mice. I-F11 gene expression levels in mouse blood were assessed under the influence of three different promoters and found to be significantly higher with TBG compared to CMV and CASI. A single tail vein or intramuscular injection of AAV8-TBG-I-F11 resulted in robust production of the enzyme, which reached concentrations of up to 1 to 2 mg/ml in mouse blood for up to 6 months. Mice containing 0.75 mg/ml or higher concentrations of I-F11 in their blood were afforded asymptomatic protection against multiple 5LD50 exposures of GD, GF, GA, and GB, a total of 9 exposures over a seven-week period. We also conducted studies showing that I-F11 is most efficacious in offering protection against GD followed by GF, GB and GA. Analysis of the mouse blood for serum chemistry and hematology parameters, and tissues by H&E staining, indicated no appreciable changes between control mice, mice overexpressing 1-F11 for 6 months, and mice surviving repeated G-agent exposures. These data suggest that AAV8-mediated catalytic bioscavenger gene therapy using 1-F11 is a safe, efficacious, and long-lasting pre-treatment strategy against G-agents.

Keywords: Gene Therapy; AAV8; Chemical Warfare Nerve Agents; Paraoxonase 1 variant I-F11; Safety; Efficacy

Published: September 2, 2018  Show citation

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Betapudi, V., Doctor, D.M., & Chilukuri, N. (2018). PARAOXONASE 1 VARIANT I-F11 GENE THERAPY USING ADENO-ASSOCIATED VIRUS8 (AAV8) OFFERS LONG-TERM PROTECTION AGAINST G-TYPE CHEMICAL WARFARE NERVE AGENTS. MMSL87(Suppl.1), 41
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