Gene therapy reduces ethanol intake in an animal model of alcohol dependence.
BACKGROUND
Some gene polymorphisms strongly protect against the development of alcoholism. A large proportion of East Asians carry a protective inactivating mutation in aldehyde dehydrogenase (ALDH2*2). These subjects display high levels of blood acetaldehyde when consuming alcohol, a condition that exerts a 66 to 99% protection against alcohol abuse and alcoholism. Present knowledge allows the incorporation of therapeutic genes that can modify the expression of disease predisposing genes, an effect that can last from months to years. In line with the above, we have tested if inhibiting the expression of the aldehyde dehydrogenase gene (ALDH2) by an anti-Aldh2 antisense gene can curtail the drive of alcohol-dependent animals to consume alcohol.


METHODS
Wistar-derived rats bred as high alcohol drinkers (UChB; Universidad de Chile Bibulous) were rendered alcohol dependent by a 2-month period of voluntary ethanol (10%) intake, subjected to a 3-day withdrawal period and further allowed access to 10% ethanol for only 1 hour each day. This condition results in a high ethanol intake (1.2 g/kg/60 min) which is 10 times higher than that of naïve UChB rats.


RESULTS
The single intravenous administration of an anti-Aldh2 antisense gene carried by an adenoviral vector reduced liver ALDH2 activity by 85% (p < 0.002) and inhibited voluntary ethanol intake by 50% (ANOVA p < 0.005) for 34 days.


CONCLUSIONS
This proof-of-principle study indicates that gene therapy approaches can be employed to achieve a long-term reduction of alcohol intake in alcohol-dependent animals and suggests that gene vectors may be developed as long-lasting therapeutic adjuncts for the treatment of alcoholism.
Ocaranza
Paula
P
Laboratory of Gene Therapy, Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile.
Quintanilla
María Elena
ME
Tampier
Lutske
L
Karahanian
Eduardo
E
Sapag
Amalia
A
Israel
Yedy
Y
D000256:Adenoviridae / Q000235:genetics; D000428:Alcohol Drinking / Q000188:drug therapy*; D000437:Alcoholism / Q000188:drug therapy*; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000818:Animals; D005260:Female; D015316:Genetic Therapy; D008099:Liver / Q000201:enzymology*; D016372:RNA, Antisense; D051381:Rats; D017208:Rats, Wistar
D016372:RNA, Antisense; D000444:Aldehyde Dehydrogenase