Gene therapy to prevent organophosphate intoxication

The specific hydrolytic activity of PON1 paraoxonase/arylesterase enzymes i n liver and blood provides a natural barrier against the entry of organopho sphate toxins into the central and peripheral nervous systems. Inherited di fferences in PON1 enzyme concentrations may determine levels of susceptibil ity to organophosphate injury in humans. To test whether boosting serum lev els of PON1 enzymes by gene therapy might provide increased protection, we compared the degree of inactivation of whole brain acetylcholinesterase of mice exposed to chlorpyrifos 4 days after intravenous injection of recombin ant adenoviruses containing PON1-LQ or PON1-LR genes or no PON1 gene. Both recombinant viruses containing PON1 genes boosted serum arylesterase concen trations by approximately 60% and significantly prevented the inactivation of brain acetylcholinesterase. Some mice were completely protected, These f indings indicate that boosting serum levels of PON1 enzymes by a gene deliv ery vector raises the threshold for organophosphate toxicity by hydrolytic destruction before the chemical can enter the brain. (C) 2001 Academic Pres s.