Gene therapy to prevent organophosphate intoxication.
The specific hydrolytic activity of PON1 paraoxonase/arylesterase enzymes in liver and blood provides a natural barrier against the entry of organophosphate toxins into the central and peripheral nervous systems. Inherited differences in PON1 enzyme concentrations may determine levels of susceptibility to organophosphate injury in humans. To test whether boosting serum levels 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 recombinant adenoviruses containing PON1-LQ or PON1-LR genes or no PON1 gene. Both recombinant viruses containing PON1 genes boosted serum arylesterase concentrations by approximately 60% and significantly prevented the inactivation of brain acetylcholinesterase. Some mice were completely protected. These findings indicate that boosting serum levels of PON1 enzymes by a gene delivery vector raises the threshold for organophosphate toxicity by hydrolytic destruction before the chemical can enter the brain.
Cowan
J
J
Molecular Host Defense Laboratory, Division of Infectious Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Sinton
C M
CM
Varley
A W
AW
Wians
F H
FH
Haley
R W
RW
Munford
R S
RS
D000110:Acetylcholinesterase / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D043303:Aryldialkylphosphatase; D001921:Brain / Q000201:enzymology; D002265:Carboxylic Ester Hydrolases / Q000097:blood / Q000235:genetics*; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D004950:Esterases / Q000097:blood / Q000235:genetics*; D015316:Genetic Therapy; D006801:Humans; D007306:Insecticides / Q000506:poisoning*; D008113:Liver Neoplasms; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D009943:Organophosphorus Compounds; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
D007306:Insecticides; D009943:Organophosphorus Compounds; D011994:Recombinant Proteins; D004950:Esterases; D002265:Carboxylic Ester Hydrolases; C019734:arylesterase; D000110:Acetylcholinesterase; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human