Gene Therapy Correction of Aldehyde Dehydrogenase 2 Deficiency

Yuki Matsumura, Katie M. Stiles, Jasmine Reid, Esther Z. Frenk, Samantha Cronin, Odelya E. Pagovich, Ronald Crystal

Research output: Contribution to journalArticle

2 Citations (Scopus)


Aldehyde dehydrogenase 2 (ALDH2) deficiency causes “Asian flush syndrome,” presenting as alcohol-induced facial flushing, tachycardia, nausea, and headaches. One of the most common hereditary enzyme deficiencies, it affects 35%–40% of East Asians and 8% of the world population. ALDH2 is the key enzyme in ethanol metabolism; with ethanol challenge, the common ALDH2*2 (E487K) mutation results in accumulation of toxic acetaldehyde. ALDH2*2 heterozygotes have increased risk for upper digestive tract cancers, compounded by smoking and drinking alcohol. We hypothesized that a one-time administration of an adeno-associated virus (AAV) gene transfer vector expressing the human ALDH2 coding sequence (AAVrh.10hALDH2) would correct the deficiency state. AAVrh.10hALDH2 was administered intravenously to Aldh2 knockout (Aldh2−/−) and Aldh2 E487K knockin homozygous (Aldh2E487K+/+) mice. Following acute ethanol ingestion, untreated ALDH2-deficient mice had elevated acetaldehyde levels and performed poorly in behavioral tests. In contrast, treated Aldh2−/− and Aldh2E487K+/+ mice had lower serum acetaldehyde levels and improved behavior. Thus, in vivo AAV-mediated ALDH2 therapy may reverse the deficiency state in ALDH2*2 individuals, eliminating the Asian flush syndrome and reducing the risk for associated disorders.

Original languageEnglish
Pages (from-to)72-82
Number of pages11
JournalMolecular Therapy - Methods and Clinical Development
Publication statusPublished - 13 Dec 2019



  • AAV
  • acetaldehyde
  • ALDH2
  • gene therapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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