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

Abstract

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
Volume15
DOIs
Publication statusPublished - 13 Dec 2019

Fingerprint

Aldehyde Dehydrogenase
Genetic Therapy
Acetaldehyde
Dependovirus
Ethanol
Poisons
Enzymes
Heterozygote
Tachycardia
Knockout Mice
Alcohol Drinking
Nausea
Headache
Gastrointestinal Tract
Eating
Smoking
Alcohols
Mutation
Serum
Population

Keywords

  • AAV
  • acetaldehyde
  • ALDH2
  • gene therapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Gene Therapy Correction of Aldehyde Dehydrogenase 2 Deficiency. / Matsumura, Yuki; Stiles, Katie M.; Reid, Jasmine; Frenk, Esther Z.; Cronin, Samantha; Pagovich, Odelya E.; Crystal, Ronald.

In: Molecular Therapy - Methods and Clinical Development, Vol. 15, 13.12.2019, p. 72-82.

Research output: Contribution to journalArticle

Matsumura, Yuki ; Stiles, Katie M. ; Reid, Jasmine ; Frenk, Esther Z. ; Cronin, Samantha ; Pagovich, Odelya E. ; Crystal, Ronald. / Gene Therapy Correction of Aldehyde Dehydrogenase 2 Deficiency. In: Molecular Therapy - Methods and Clinical Development. 2019 ; Vol. 15. pp. 72-82.
@article{593741bfe15d4502b8582e09ab277420,
title = "Gene Therapy Correction of Aldehyde Dehydrogenase 2 Deficiency",
abstract = "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.",
keywords = "AAV, acetaldehyde, ALDH2, gene therapy",
author = "Yuki Matsumura and Stiles, {Katie M.} and Jasmine Reid and Frenk, {Esther Z.} and Samantha Cronin and Pagovich, {Odelya E.} and Ronald Crystal",
year = "2019",
month = "12",
day = "13",
doi = "10.1016/j.omtm.2019.08.004",
language = "English",
volume = "15",
pages = "72--82",
journal = "Molecular Therapy - Methods and Clinical Development",
issn = "2329-0501",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Gene Therapy Correction of Aldehyde Dehydrogenase 2 Deficiency

AU - Matsumura, Yuki

AU - Stiles, Katie M.

AU - Reid, Jasmine

AU - Frenk, Esther Z.

AU - Cronin, Samantha

AU - Pagovich, Odelya E.

AU - Crystal, Ronald

PY - 2019/12/13

Y1 - 2019/12/13

N2 - 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.

AB - 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.

KW - AAV

KW - acetaldehyde

KW - ALDH2

KW - gene therapy

UR - http://www.scopus.com/inward/record.url?scp=85072865860&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072865860&partnerID=8YFLogxK

U2 - 10.1016/j.omtm.2019.08.004

DO - 10.1016/j.omtm.2019.08.004

M3 - Article

AN - SCOPUS:85072865860

VL - 15

SP - 72

EP - 82

JO - Molecular Therapy - Methods and Clinical Development

JF - Molecular Therapy - Methods and Clinical Development

SN - 2329-0501

ER -