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.

Systemic Adeno-Associated Virus-Mediated Gene Therapy Prevents the Multiorgan Disorders Associated with Aldehyde Dehydrogenase 2 Deficiency and Chronic Ethanol Ingestion

“…We have previously demonstrated that the acute effects of ethanol in these murine models of ALDH2 deficiency (the mouse equivalent of the ''Asian flush syndrome'') can be corrected by systemic liver-directed serotype rh.10 adenoassociated virus (AAVrh.10hALDH2)-mediated delivery of the normal human ALDH2 coding sequence. 30 In this study, we have extended these observations in these two murine models of ALDH2 deficiency to assess whether this therapy will prevent the diseases associated with chronic ethanol ingestion. Strikingly, the therapy prevents chronic alcoholmediated body weight loss, anemia, poor locomotion, skin pigmentation, elevated serum acetaldehyde, and liver malondialdehyde (MDA) levels.…”

“…S2). 30 The HA tag was used for differentiating between human and mouse ALDH2 proteins because the mouse and human amino acid sequences are 96% homologous (NCBI Homologene: https://www.ncbi.nlm.nih.gov/homologene/55480).…”

Electrolyzed Hydrogen Water Protects against Ethanol-Induced Cytotoxicity by Regulating Aldehyde Metabolism-Associated Enzymes in the Hepatic Cell Line HepG2

“…It has been reported that not only the activity of ADH but also mRNA levels and protein levels are altered in ethanol feeding experiments in rats [ 24 ]. In addition, an analysis using Aldh2 -/- mice, in which human ALDH2 was overexpressed, reported that ethanol administration decreased the amount of acetaldehyde in the blood [ 25 ]. Whether EHW and hydrogen water directly regulate ADH and ALDH enzymatic activities, as well as gene expression and/or protein levels of ADH and ALDH, will need to be clarified in the future.…”

My Pathway to Gene Therapy

“…Most, but not all, use AAV vectors. Among these programs are AAV-based therapies of experimental models of chronic traumatic encephalopathy, 56 AAT deficiency, 57 aldehyde dehydrogenase 2 deficiency, 58,59 Friedrich's ataxia, 60 metachromatic leukodystrophy, 61 CLN3 disease, 62 Niemann-Pick type C2 disease, 63 hypereosinophilia, 64 hereditary angioedema, 65 severe immunoglobulin E-mediated allergy, 65 oxidant-mediated disorders, 66 and a variety of cancer-related disorders, including glioblastoma, 67,68 ovarian cancer, 69 and metastatic lung disease. 70,71 Finally, we have programs using gene transfer vectors to induce antibodies against addictive drugs [72][73][74][75][76][77] and infectious agents.…”