title: 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.
authors: Laboratory of Gene Therapy, Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile.
authors: Paula
authors: P
authors: Ocaranza
authors: María Elena
authors: ME
authors: Quintanilla
authors: Lutske
authors: L
authors: Tampier
authors: Eduardo
authors: E
authors: Karahanian
authors: Amalia
authors: A
authors: Sapag
authors: Yedy
authors: Y
authors: Israel
mesh_terms: 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
chemical_list: D016372:RNA, Antisense; D000444:Aldehyde Dehydrogenase