Alcoholism is a complex disease affecting hundreds of millions of people worldwide¹. Despite having devastating consequences on physical and mental health, and indirectly impacting families and society, treatment options are limited and often ineffective². Current evidence suggests that environmental and genetic factors both equally influence an individual’s susceptibility to alcoholism³.

Genetics of alcohol metabolism

Interestingly, people with certain genotypes are significantly less likely to become alcoholic, likely due to unpleasant, aversive effects they experience when consuming alcohol^4-7. The most well-understood examples are variants of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes. These enzymes are sequentially involved in metabolizing ethanol to acetaldehyde and then acetate. Individuals who carry mutations in these ALDH genes can accumulate acetaldehyde in the blood after ethanol consumption producing strong effects, including facial flushing, hypotension, and dizziness.

Modifying alcohol metabolism

Some researchers are now proposing to develop a gene therapy-based treatment for alcoholism based on the effect of mutant ALDH2. In a new paper, Sanchez et al. describe an shRNA-expressing AAV vector system designed to knock down mitochondrial ALDH2⁸. Their goal is to mimic the effects of inactive ALDH2*2 alleles, which are common in Asian populations and are believed to reduce alcoholism risk. The research team showed effective knockdown of ALDH2 in human liver cells, which lead to increased acetaldehyde levels after ethanol exposure. They believe that these elevated acetaldehyde levels could effectively prevent people from engaging in alcoholic behaviors. The effect of ALDH2 knockdown in humans should be like that of the drug Antabuse (disulfiram), but without issues of inconsistent patient compliance, and knockdown may have fewer off-target activities. The potential for developing vector-based treatments for alcohol addiction will likely lead to heated ethical debates, but also may provide freedom for millions of people suffering from alcohol dependency.

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References

1. Global status report on alcohol and health 2014. World Health Organization. 2014. p. s8,51. ISBN 9789240692763.
2. Volkow, N. D. (2008). Drugs, brains, and behavior: The science of addiction. National Institutue on Drug Abuse.
3. Enoch MA. Genetic influences on the development of alcoholism. Curr Psychiatry Rep. 2013 Nov;15(11):412.
4. Rivetti di Val Cervo P, Romanov RA, Spigolon G, Masini D, Martín-Montañez E, Toledo EM, La Manno G, Feyder M, Pifl C, Ng YH, Sánchez SP, Linnarsson S, Wernig M, Harkany T, Fisone G, Arenas E. Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model. Nat Biotechnol. 2017 May;35(5):444-452.
5. Oroszi G, Goldman D. Alcoholism: genes and mechanisms. Pharmacogenomics. 2004 Dec;5(8):1037-48.
6. Chen CC, Lu RB, Chen YC, Wang MF, Chang YC, Li TK, Yin SJ. Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism. Am J Hum Genet. 1999 Sep;65(3):795-807
7. Peng GS, Yin SJ. Effect of the allelic variants of aldehyde dehydrogenase ALDH2*2 and alcohol dehydrogenase ADH1B*2 on blood acetaldehyde concentrations. Hum Genomics. 2009 Jan;3(2):121-7.
8. Sanchez AC, Li C, Andrews B, Asenjo JA, Samulski RJ. AAV Gene Therapy for Alcoholism: Inhibition of Mitochondrial Aldehyde Dehydrogenase Enzyme Expression in Hepatoma Cells. Hum Gene Ther. 2017 Sep;28(9):717-725.