Gene Therapy Reduces Ethanol Intake in an Animal Model of Alcohol Dependence

ABSTRACT

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.