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• W2970978045 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. 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. Aldehyde dehydrogenase 2 (ALDH2) deficiency is one of the most common hereditary disorders, affecting 560 million people, 8% of the world population.1Brooks P.J. Enoch M.A. Goldman D. Li T.K. Yokoyama A. The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption.PLoS Med. 2009; 6: e50Crossref PubMed Scopus (326) Google Scholar The highest prevalence (35%–45%) is in people of East Asian descent.2Chen C.H. Ferreira J.C. Gross E.R. Mochly-Rosen D. Targeting aldehyde dehydrogenase 2: new therapeutic opportunities.Physiol. Rev. 2014; 94: 1-34Crossref PubMed Scopus (371) Google Scholar, 3Gross E.R. Zambelli V.O. Small B.A. Ferreira J.C. Chen C.H. Mochly-Rosen D. A personalized medicine approach for Asian Americans with the aldehyde dehydrogenase 2*2 variant.Annu. Rev. Pharmacol. Toxicol. 2015; 55: 107-127Crossref PubMed Scopus (89) Google Scholar ALDH2 belongs to a superfamily of enzymes that play key roles in the metabolism of endogenous and exogenous aldehydes.4Yoshida A. Rzhetsky A. Hsu L.C. Chang C. Human aldehyde dehydrogenase gene family.Eur. J. Biochem. 1998; 251: 549-557Crossref PubMed Scopus (390) Google Scholar The enzyme is targeted to mitochondria; while ubiquitously expressed in all tissues at low levels, ALDH2 expression is most abundant in the liver, the primary organ of ethanol metabolism.5Koivisto T. Salaspuro M. Aldehyde dehydrogenases of the rat colon: comparison with other tissues of the alimentary tract and the liver.Alcohol. Clin. Exp. Res. 1996; 20: 551-555Crossref PubMed Scopus (52) Google Scholar, 6Stewart M.J. Malek K. Crabb D.W. Distribution of messenger RNAs for aldehyde dehydrogenase 1, aldehyde dehydrogenase 2, and aldehyde dehydrogenase 5 in human tissues.J. Investig. Med. 1996; 44: 42-46PubMed Google Scholar ALDH2 is the second enzyme in the ethanol metabolism pathway and functions to convert the toxic intermediate acetaldehyde to nontoxic acetate (Figure S1).7Klyosov A.A. Rashkovetsky L.G. Tahir M.K. Keung W.M. Possible role of liver cytosolic and mitochondrial aldehyde dehydrogenases in acetaldehyde metabolism.Biochemistry. 1996; 35: 4445-4456Crossref PubMed Scopus (156) Google Scholar Mutations in ALDH2 that reduce the oxidizing ability of the enzyme result in accumulation of serum acetaldehyde.8Chen C.H. Sun L. Mochly-Rosen D. Mitochondrial aldehyde dehydrogenase and cardiac diseases.Cardiovasc. Res. 2010; 88: 51-57Crossref PubMed Scopus (159) Google Scholar, 9Jin S. Chen J. Chen L. Histen G. Lin Z. Gross S. Hixon J. Chen Y. Kung C. Chen Y. et al.ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis.Proc. Natl. Acad. Sci. USA. 2015; 112: 9088-9093Crossref PubMed Scopus (52) Google Scholar The ALDH2 enzyme is a tetramer, and the mutant protein functions as a dominant-negative.10Weiner H. Wei B. Zhou J. Subunit communication in tetrameric class 2 human liver aldehyde dehydrogenase as the basis for half-of-the-site reactivity and the dominance of the oriental subunit in a heterotetramer.Chem. Biol. Interact. 2001; 130-132: 47-56Crossref PubMed Scopus (22) Google Scholar, 11Larson H.N. Zhou J. Chen Z. Stamler J.S. Weiner H. Hurley T.D. Structural and functional consequences of coenzyme binding to the inactive asian variant of mitochondrial aldehyde dehydrogenase: roles of residues 475 and 487.J. Biol. Chem. 2007; 282: 12940-12950Crossref PubMed Scopus (86) Google Scholar Heterozygotes have < 50% ALDH2 enzymatic activity and homozygotes < 4%.12Kitagawa K. Kawamoto T. Kunugita N. Tsukiyama T. Okamoto K. Yoshida A. Nakayama K. Nakayama K. Aldehyde dehydrogenase (ALDH) 2 associates with oxidation of methoxyacetaldehyde; in vitro analysis with liver subcellular fraction derived from human and Aldh2 gene targeting mouse.FEBS Lett. 2000; 476: 306-311Crossref PubMed Scopus (132) Google Scholar, 13Lai C.L. Yao C.T. Chau G.Y. Yang L.F. Kuo T.Y. Chiang C.P. Yin S.J. Dominance of the inactive Asian variant over activity and protein contents of mitochondrial aldehyde dehydrogenase 2 in human liver.Alcohol. Clin. Exp. Res. 2014; 38: 44-50Crossref PubMed Scopus (60) Google Scholar Mutations in ALDH2 are responsible for the Asian flush syndrome, characterized by facial flushing, headache, nausea, dizziness, and cardiac palpitations after consumption of alcoholic beverages.3Gross E.R. Zambelli V.O. Small B.A. Ferreira J.C. Chen C.H. Mochly-Rosen D. A personalized medicine approach for Asian Americans with the aldehyde dehydrogenase 2*2 variant.Annu. Rev. Pharmacol. Toxicol. 2015; 55: 107-127Crossref PubMed Scopus (89) Google Scholar, 14Peng G.S. Chen Y.C. Tsao T.P. Wang M.F. Yin S.J. Pharmacokinetic and pharmacodynamic basis for partial protection against alcoholism in Asians, heterozygous for the variant ALDH2*2 gene allele.Pharmacogenet. Genomics. 2007; 17: 845-855Crossref PubMed Scopus (65) Google Scholar The syndrome is caused by elevated blood acetaldehyde levels resulting from reduced ALDH2 enzymatic activity of the mutant protein.9Jin S. Chen J. Chen L. Histen G. Lin Z. Gross S. Hixon J. Chen Y. Kung C. Chen Y. et al.ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis.Proc. Natl. Acad. Sci. USA. 2015; 112: 9088-9093Crossref PubMed Scopus (52) Google Scholar The most common mutation is a glutamic acid-to-lysine substitution at position 487 (E487K), designated the ALDH2*2 allele.3Gross E.R. Zambelli V.O. Small B.A. Ferreira J.C. Chen C.H. Mochly-Rosen D. A personalized medicine approach for Asian Americans with the aldehyde dehydrogenase 2*2 variant.Annu. Rev. Pharmacol. Toxicol. 2015; 55: 107-127Crossref PubMed Scopus (89) Google Scholar, 15Luo H.R. Wu G.S. Pakstis A.J. Tong L. Oota H. Kidd K.K. Zhang Y.P. Origin and dispersal of atypical aldehyde dehydrogenase ALDH2487Lys.Gene. 2009; 435: 96-103Crossref PubMed Scopus (60) Google Scholar In addition to the acute Asian flush syndrome, the ALDH2*2 variant allele is associated with a variety of neurologic, endocrine, cardiovascular, and dermatologic disorders, aberrant drug metabolism, and importantly, a marked increase in the risk of upper aerodigestive tract cancer of the oral cavity, pharynx, larynx, and esophagus.2Chen C.H. Ferreira J.C. Gross E.R. Mochly-Rosen D. Targeting aldehyde dehydrogenase 2: new therapeutic opportunities.Physiol. Rev. 2014; 94: 1-34Crossref PubMed Scopus (371) Google Scholar, 3Gross E.R. Zambelli V.O. Small B.A. Ferreira J.C. Chen C.H. Mochly-Rosen D. A personalized medicine approach for Asian Americans with the aldehyde dehydrogenase 2*2 variant.Annu. Rev. Pharmacol. Toxicol. 2015; 55: 107-127Crossref PubMed Scopus (89) Google Scholar Cigarette smoke also contains acetaldehyde, and the combination of cigarette smoking and alcohol consumption by individuals carrying the ALDH2*2 allele represents a very high cancer risk (odds ratio 50:1) with a 25-year earlier onset of esophageal carcinoma.1Brooks P.J. Enoch M.A. Goldman D. Li T.K. Yokoyama A. The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption.PLoS Med. 2009; 6: e50Crossref PubMed Scopus (326) Google Scholar, 16Lee C.H. Wu D.C. Wu I.C. Goan Y.G. Lee J.M. Chou S.H. Chan T.F. Huang H.L. Hung Y.H. Huang M.C. et al.Genetic modulation of ADH1B and ALDH2 polymorphisms with regard to alcohol and tobacco consumption for younger aged esophageal squamous cell carcinoma diagnosis.Int. J. Cancer. 2009; 125: 1134-1142Crossref PubMed Scopus (35) Google Scholar, 17Morita M. Kumashiro R. Kubo N. Nakashima Y. Yoshida R. Yoshinaga K. Saeki H. Emi Y. Kakeji Y. Sakaguchi Y. et al.Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: epidemiology, clinical findings, and prevention.Int. J. Clin. Oncol. 2010; 15: 126-134Crossref PubMed Scopus (146) Google Scholar ALDH2 deficiency has been modeled in mice, and the molecular and clinical phenotypes closely mimic the human disorder.12Kitagawa K. Kawamoto T. Kunugita N. Tsukiyama T. Okamoto K. Yoshida A. Nakayama K. Nakayama K. Aldehyde dehydrogenase (ALDH) 2 associates with oxidation of methoxyacetaldehyde; in vitro analysis with liver subcellular fraction derived from human and Aldh2 gene targeting mouse.FEBS Lett. 2000; 476: 306-311Crossref PubMed Scopus (132) Google Scholar, 18Zambelli V.O. Gross E.R. Chen C.H. Gutierrez V.P. Cury Y. Mochly-Rosen D. Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain.Sci. Transl. Med. 2014; 6: 251ra118Crossref PubMed Scopus (72) Google Scholar The Aldh2 knockout mouse (Aldh2−/−) expresses no detectable ALDH2 protein or enzymatic activity.12Kitagawa K. Kawamoto T. Kunugita N. Tsukiyama T. Okamoto K. Yoshida A. Nakayama K. Nakayama K. Aldehyde dehydrogenase (ALDH) 2 associates with oxidation of methoxyacetaldehyde; in vitro analysis with liver subcellular fraction derived from human and Aldh2 gene targeting mouse.FEBS Lett. 2000; 476: 306-311Crossref PubMed Scopus (132) Google Scholar After ethanol administration, Aldh2−/− mice have significantly higher levels of blood acetaldehyde than wild-type mice, and exposure to 2 g/kg ethanol for 8 days results in weight loss and increased mortality.19Isse T. Oyama T. Matsuno K. Uchiyama I. Kawamoto T. Aldehyde dehydrogenase 2 activity affects symptoms produced by an intraperitoneal acetaldehyde injection, but not acetaldehyde lethality.J. Toxicol. Sci. 2005; 30: 315-328Crossref PubMed Scopus (23) Google Scholar, 20Oyama T. Isse T. Ogawa M. Muto M. Uchiyama I. Kawamoto T. Susceptibility to inhalation toxicity of acetaldehyde in Aldh2 knockout mice.Front. Biosci. 2007; 12: 1927-1934Crossref PubMed Scopus (28) Google Scholar The Aldh2 E487K knockin mouse (Aldh2E487K+/+) has the lysine 487 mutation from the human ALDH2*2 allele.18Zambelli V.O. Gross E.R. Chen C.H. Gutierrez V.P. Cury Y. Mochly-Rosen D. Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain.Sci. Transl. Med. 2014; 6: 251ra118Crossref PubMed Scopus (72) Google Scholar These mice accumulate high acetaldehyde levels in the blood when challenged with ethanol, have reduced enzymatic ALDH2 activity, and exhibit increased ethanol-related behavioral abnormalities.9Jin S. Chen J. Chen L. Histen G. Lin Z. Gross S. Hixon J. Chen Y. Kung C. Chen Y. et al.ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis.Proc. Natl. Acad. Sci. USA. 2015; 112: 9088-9093Crossref PubMed Scopus (52) Google Scholar, 18Zambelli V.O. Gross E.R. Chen C.H. Gutierrez V.P. Cury Y. Mochly-Rosen D. Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain.Sci. Transl. Med. 2014; 6: 251ra118Crossref PubMed Scopus (72) Google Scholar We hypothesized that genetic modification of the ALDH2-deficient liver to express the normal human ALDH2 coding sequence would increase the oxidizing ability of the ALDH2 tetrameric enzyme toward wild-type levels, resulting in decreased acetaldehyde accumulation and a reduction in behavioral symptoms associated with ethanol-induced acetaldehyde toxicity. The data demonstrate that both knockout and knockin ALDH2-deficient mice that were administered a single intravenous dose of a serotype rh.10 adeno-associated virus (AAV) coding for the wild-type human ALDH2 gene showed enhanced liver ALDH2 enzymatic activity and, when challenged with ethanol, demonstrated reduced serum acetaldehyde accumulation and a marked reduction of behavioral abnormalities. Because mouse and human ALDH2 protein sequences are 96% homologous (NCBI HomoloGene: https://www.ncbi.nlm.nih.gov/homologene/55480), the AAVrh.10 vector encoding the cDNA of human ALDH2 included a hemagglutinin (HA) tag to facilitate detection (Figure S2). For the initial assessment of the in vivo expression of hALDH2 from AAVrh.10hALDH2, wild-type C57BL/6 mice (n = 4) were administered a single dose (1011 genome copies [gc]) intravenously of AAVrh.10hALDH2, AAVrh.10control (an identical construct to AAVrh.10hALDH2 but with an irrelevant transgene), or PBS. Livers were harvested at 2, 4, 12, and 24 weeks post-administration and analyzed for hALDH2 mRNA and protein expression. Sustained high levels of hALDH2 mRNA of at least 2.2 × 104 ± 5.0 × 103 gc/μg total RNA were detected in the liver of AAVrh.10hALDH2-treated mice (Figures 1A and S3). No hALDH2 mRNA was detected in PBS or AAVrh.10control-treated mice. Levels of hALDH2 protein detected in the livers mirrored the mRNA levels, with vector-derived hALDH2 detected in the liver of mice treated with AAVrh.10hALDH2 at 2, 4, 12, and 24 weeks post-administration but not in PBS-treated mice (Figure 1B). Long-term expression of hALDH2 has also been observed in Aldh2−/− and Aldh2E487K+/+ mice out to 16 weeks post-administration.21Matsumura Y. Hart F. Pagovich O.E. Stiles K.M. Crystal R.G. AAV-Mediated Gene Therapy for Aldehyde Dehydrogenase 2 Deficiency Reduces Acetaldehyde-Related DNA Adduct and Damage of Esophagus.Mol. Ther. 2019; 27: 373-374Google Scholar To assess the ability of AAVrh.10hALDH2 to correct ALDH2 deficiency, Aldh2−/− and Aldh2E487K+/+ mice were treated with AAVrh.10hALDH2 or AAVrh.10control (1011 gc) by intravenous administration. Four weeks later, hALDH2 mRNA, protein, and enzymatic activity levels were analyzed in the liver. Liver hALDH2 mRNA expression of AAVrh.10hALDH2-treated Aldh2−/− and Aldh2E487K+/+ mice was significantly higher than in mice administered AAVrh.10control (Figure 2A, Aldh2−/−, p < 10−4; Aldh2E487K+/+, p < 10−4, Figure S4A). Protein expression assessed by western analysis demonstrated hALDH2 protein only in AAVrh.10hALDH2-treated Aldh2−/− and Aldh2E487K+/+ mice and not in AAVrh.10control-treated mice (Figure 2B, Aldh2−/−, p < 0.03; Aldh2E487K+/+, p < 0.05, Figure S4B). Immunohistochemical staining in AAVrh.10hALDH2-treated Aldh2−/− and Aldh2E487K+/+ mice mirrored the western analysis. hALDH2-positive cells were found mainly around hepatic and portal veins in AAVrh.10hALDH2-treated mice, while no positive cells were observed in AAVrh.10control-treated mice (Figure 2C). Additionally, the Aldh2−/− and Aldh2E487K+/+ mice treated with AAVrh.10hALDH2 demonstrated increased liver ALDH2 enzymatic activity compared to untreated mice (Aldh2−/−, p < 10−12; Aldh2E487K+/+, p < 0.0004), with levels similar to wild-type C57BL/6 mice (p > 0.9; Figures 2D and S4C). Western analysis using an anti-ALDH2 antibody that recognizes both mouse and human ALDH2 showed that levels of vector-derived hALDH2-HA was much higher than endogenous mALDH2 in Aldh2E487K+/+ mice (Figure S5). Aldh2−/− and Aldh2E487K+/+ mice both developed elevated levels of blood acetaldehyde and behavioral abnormalities in response to acute ethanol challenge. To assess whether AAVrh.10hALDH2-mediated therapy could alleviate the effects of ethanol challenge in ALDH2 deficiency, both mouse models were administered a single dose of ethanol (4 g/kg) or water by intragastric gavage 4 weeks after administration of AAVrh.10hALDH2 or AAVrh.10control. Serum acetaldehyde levels of AAVrh.10hALDH2-treated Aldh2−/− and Aldh2E487K+/+ mice (n = 5) at 6 hr post-ethanol-gavage were significantly lower than that of AAVrh.10control mice (Figure 3, Aldh2−/−, p < 0.03; Aldh2E487K+/+, p < 0.02, Figure S6). High variability in serum acetaldehyde levels was observed in AAVrh.10control-treated ALDH2-deficient mice; however, this is consistent with studies in human ALDH2*2 individuals after controlled ethanol ingestion.14Peng G.S. Chen Y.C. Tsao T.P. Wang M.F. Yin S.J. Pharmacokinetic and pharmacodynamic basis for partial protection against alcoholism in Asians, heterozygous for the variant ALDH2*2 gene allele.Pharmacogenet. Genomics. 2007; 17: 845-855Crossref PubMed Scopus (65) Google Scholar All mice gavaged with water had low levels of blood acetaldehyde at the same time point. Behavioral assessments were performed 4 weeks after AAVrh.10hALDH2 or AAVrh.10control administration to Aldh2−/− and Aldh2E487K+/+ mice (n = 10) before and 0.5, 2, 6, 10, and 24 hr post-ethanol administration by intragastric gavage (Figure S7; Tables S1–S8). At 6 hr post-ethanol-gavage, AAVrh.10hALDH2 treated Aldh2−/− and Aldh2E487K+/+ mice showed fewer behavioral abnormalities using an observational behavior score (Figures 4A and S7A) and had higher body temperature closer to normal (Figures 4B and S7B). Acute acetaldehyde toxicity results in sedation, hypoactivity, and lethargy.2Chen C.H. Ferreira J.C. Gross E.R. Mochly-Rosen D. Targeting aldehyde dehydrogenase 2: new therapeutic opportunities.Physiol. Rev. 2014; 94: 1-34Crossref PubMed Scopus (371) Google Scholar, 22Quertemont E. Tambour S. Tirelli E. The role of acetaldehyde in the neurobehavioral effects of ethanol: a comprehensive review of animal studies.Prog. Neurobiol. 2005; 75: 247-274Crossref PubMed Scopus (131) Google Scholar AAVrh.10hALDH2-treated mice performed significantly better than mice administered the control vector in tests measuring ambulatory activity such as distance traveled on a balance beam (Figures 4C and S7C) and distance traveled in an open-field chamber (Figures 4D and S7D). Additionally, increased rearing or vertical activity was observed in AAVrh.10hALDH2 vector-treated mice, although their recovery was significantly slower compared with C57BL/6 (Figures 4E and S7E). Mice were also evaluated in tests of motor coordination and strength. AAVrh.10hALDH2-treated Aldh2−/− and Aldh2E487K+/+ mice took less time to cross a skinny beam by 46% and 72%, respectively (Figures 4F and S7F; Video S1). The time to failure for balance on a skinny rod increased by 2.8 and 5.8 s for AAVrh.10hALDH2-treated Aldh2−/− and Aldh2E487K+/+ treated mice, respectively, as compared to control vector-treated mice (Figures 4G and S7G; Video S2). In the screen-climb test, the time to goal was reduced by 73% for Aldh2−/− and 78% for Aldh2E487K+/+ mice treated with AAVrh.10hALDH2 vector compared with mice administered AAVrh.10control (Figures 4H and S7H; Video S3). The functional composite behavior score represents the cumulative assessment of behavior described in Figures 4C–4H; a higher score is associated with poorer performance (Table S1). Overall, AAVrh.10hALDH2-treated mice had significantly lower scores than mice treated with control vector (Figures 4I and S7I). The levels of serum acetaldehyde correlated well with the observational behavior score (Figure 5A) and body temperature (Figure 5B), despite individual variability in serum acetaldehyde in the AAVrh.10control-treated groups. There was no significant difference between the treatment of Aldh2−/− and Aldh2E487K+/+ mice (Table S6). Together, the results from these assessments suggest that treatment with AAVrh.10hALDH2 can alleviate both biochemical and behavioral symptoms of acute ethanol stress in ALDH2 deficiency.Figure 5Correlation of Observational Behavior Score and Body Temperature with Serum Acetaldehyde LevelsShow full captionSerum acetaldehyde levels, observational behavior score, and body temperature of Aldh2−/−, Aldh2E487K+/+, and C57BL/6 mice (n = 5/group) were measured 6 hr after intragastric ethanol exposure (4 g/kg body weight) and 4 weeks after intravenous administration of AAVrh.10hALDH2 (1011 gc) or AAVrh.10control (1011 gc). C57BL/6 mice were intravenously administered PBS. (A) Observational behavior score (from Figure 4A) versus serum acetaldehyde levels (from Figure 3) of individual mice. (B) Body temperature (from Figure 4B) versus serum acetaldehyde levels (from Figure 3) of individual mice.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Serum acetaldehyde levels, observational behavior score, and body temperature of Aldh2−/−, Aldh2E487K+/+, and C57BL/6 mice (n = 5/group) were measured 6 hr after intragastric ethanol exposure (4 g/kg body weight) and 4 weeks after intravenous administration of AAVrh.10hALDH2 (1011 gc) or AAVrh.10control (1011 gc). C57BL/6 mice were intravenously administered PBS. (A) Observational behavior score (from Figure 4A) versus serum acetaldehyde levels (from Figure 3) of individual mice. (B) Body temperature (from Figure 4B) versus serum acetaldehyde levels (from Figure 3) of individual mice. eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI1ZDlhNDlhMDZmNTZiYzAwZTk5NjRjNTdlYTNhMmVjMSIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc4NDM3MTQ1fQ.os2fLm9dxUcg48-hNOGg1Yfk-NLt73h4raAl2iyAaYTGorIpj2xoIzXkbt4sgImGyGuO7a6jhGJm1BRzK3eXnPOnmKH-hkavtG3G7iG8kQsvmeS8Og1mzs8Tp1J4Z4vWcQdEJeni3JP8107wj5KymQf9zf2Lone0uik4bcVplZyZpTXBUOR7LU4JCbnTC5bqyMU5yKGr15577jb99zPiWCGklrJKxOtmTIr_7e_8RZxrH0TTzdp2AUSq1eHN5n0TI2J1a8SJA9LSYtvltUpiZF-tk7AgR9kxqEmD3Ny5m1yL-1aqqzx7fIez4S92rWcMfiQDsEdjQ30LIsK1nzIn5Q Download .mp4 (9.58 MB) Help with .mp4 files Video S1. Representative Skinny-Beam Behavioral Test of Aldh2E487K+/+ Mouse Pre-ethanol (Top) and 6 hr Post-intragastric Gavage with 4 g/kg Ethanol (Bottom)Left panels, AAVrh.10control treated; right panels, AAVrh.10hALDH2 treated. eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI4NzVkOGMxOTFlOTJkMTUwNzBlZDMxNjhjYWRjYjk4NCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc4NDM3MTQ1fQ.qCniVZkqUOSyo0KECWvidBhgTo_K_d1-Sl3wT794ryYI3jskhWVhei-3e_3VixB_UYqZB87nHpJPmRubTzjAyRIWPhMn7DKzO0OUIYeGiAB2ORSDjhpa87Gdb-zup3tRSFW649NDIcbWNoQ9FpqArY8EQL4vPbVlJr1eEEYATAo24UinemR9zy5v5NvPy8IybUJ4DfFx7zadaDqoDHPIZN32Hi35gjvGrTxFOty-ju2FW-JK-U10OBjxaNACTRubAGD2VLwbZKHvK47KS1LtJr2yCZ8P_L7e5Fpk7BHJbNcTK0tNJN74o9hXdi5M2H0u7UKX6SgWD6mL2F_27dQ5iQ Download .mp4 (8.02 MB) Help with .mp4 files Video S2. Representative Skinny-Rod Behavioral Test of Aldh2E487K+/+ Mouse Pre-ethanol (Top) and 6 hr Post-intragastric Gavage with 4 g/kg Ethanol (Bottom)Left panels, AAVrh.10control treated; right panels, AAVrh.10hALDH2 treated. eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI0MmM2OTcxODJhMmUzYTM4YWRhYjE2OWU2NWExNjBiZCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc4NDM3MTQ1fQ.Xt7zr6dhb8Pf1A_6cVdRPRlzbbeeqi7evRPDKqJraDN_gvbNE2KKxmWZdMfrdP82TRqm-hYpNL6KYsa9TFETmROh5M9hk1q5Rhz5S9qQmJPOkws6f3VnwCFb9PTJ93782cujszMUkAnzs5kf5RtwuBT3WfhH0CfgeTxOfJMrDuW_1gEayyk2daTM0Jj2kJiTJgVcrAzJUL_Ykg-9uiCsTH-QPsryeUIj1ShMtl11JtTAeyCt1UwDmZeLcAA4aSSHDHzU2YCz_XiC7IMQ5GxVo-nvRKBboWaDNT4jjQj5ukgeSWXD2nZ0dCLwfs71iYLkYzkd2xj6XqoRDt_DEwbGAg Download .mp4 (13.85 MB) Help with .mp4 files Video S3. Representative Screen-Climb Behavioral Test of Aldh2E487K+/+ Mouse Pre-ethanol (Top) and 6 hr Post-intragastric Gavage with 4 g/kg Ethanol (Bottom)Left panels, AAVrh.10control treated; right panels, AAVrh.10hALDH2 treated. ALDH2 deficiency is one of the most common inherited enzyme deficiencies worldwide.1Brooks P.J. Enoch M.A. Goldman D. Li T.K. Yokoyama A. The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption.PLoS Med. 2009; 6: e50Crossref PubMed Scopus (326) Google Scholar, 2Chen C.H. Ferreira J.C. Gross E.R. Mochly-Rosen D. Targeting aldehyde dehydrogenase 2: new therapeutic opportunities.Physiol. Rev. 2014; 94: 1-34Crossref PubMed Scopus (371) Google Scholar ALDH2 is a key enzyme for ethanol metabolism, and mutations that reduce the oxidizing ability of the enzyme result in an accumulation of toxic acetaldehyde.2Chen C.H. Ferreira J.C. Gross E.R. Mochly-Rosen D. Targeting aldehyde dehydrogenase 2: new therapeutic opportunities.Physiol. Rev. 2014; 94: 1-34Crossref PubMed Scopus (371) Google Scholar, 9Jin S. Chen J. Chen L. Histen G. Lin Z. Gross S. Hixon J. Chen Y. Kung C. Chen Y. et al.ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis.Proc. Natl. Acad. Sci. USA. 2015; 112: 9088-9093Crossref PubMed Scopus (52) Google Scholar The most common genetic variant, referred to as the ALDH2*2 allele, is caused by a glutamic acid-to-lysine substitution at position 487 (E487K).15Luo H.R. Wu G.S. Pakstis A.J. Tong L. Oota H. Kidd K.K. Zhang Y.P. Origin and dispersal of atypical aldehyde dehydrogenase ALDH2487Lys.Gene. 2009; 435: 96-103Crossref PubMed Scopus (60) Google Scholar The E487K mutation results in greatly reduced enzymatic activity and ability to process acetaldehyde in heterozygote and homozygote individuals.12Kitagawa K. Kawamoto T. Kunugita N. Tsukiyama T. Okamoto K. Yoshida A. Nakayama K. Nakayama K. Aldehyde dehydrogenase (ALDH) 2 associates with oxidation of methoxyacetaldehyde; in vitro analysis with liver subcellular fraction derived from human and Aldh2 gene targeting mouse.FEBS Lett. 2000; 476: 306-311Crossref PubMed Scopus (132) Google Scholar, 13Lai C.L. Yao C.T. Chau G.Y. Yang L.F. Kuo T.Y. Chiang C.P. Yin S.J. Dominance of the inactive Asian variant over activity and protein contents of mitochondrial aldehyde dehydrogenase 2 in human liver.Alcohol. Clin. Exp. Res. 2014; 38: 44-50Crossref PubMed Scopus (60) Google Scholar Mutations of ALDH2 and the resulting accumulation of acetaldehyde in the blood with alcohol ingestion is the cause of the Asian flush syndrome. ALDH2 deficiency has also been linked to multiple chronic diseases, including aerodigestive tract cancers, diabetes, and cardiovascular and neurodegenerative diseases.1Brooks P.J. Enoch M.A. Goldman D. Li T.K. Yokoyama A. The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption.PLoS Med. 2009; 6: e50Crossref PubMed Scopus (326) Google Scholar, 2Chen C.H. Ferreira J.C. Gross E.R. Mochly-Rosen D. Targeting aldehyde dehydrogenase 2: new therapeutic opportunities.Physiol. Rev. 2014; 94: 1-34Crossref PubMed Scopus (371) Google Scholar, 3Gross E.R. Zambelli V.O. Small B.A. Ferreira J.C. Chen C.H. Mochly-Rosen D. A personalized medicine approach for Asian Americans with the aldehyde dehydrogenase 2*2 variant.Annu. Rev. Pharmacol. Toxicol. 2015; 55: 107-127Crossref PubMed Scopus (89) Google Scholar, 14Peng G.S. Chen Y.C. Tsao T.P. Wang M.F. Yin S.J. Pharmacokinetic and pharmacodynamic basis for partial protection against alcoholism in Asians, heterozygous for the variant ALDH2*2 gene allele.Pharmacogenet. Genomics. 2007; 17: 845-855Crossref PubMed Scopus (65) Google Scholar, 23Yokoyama A. Muramatsu T. Ohmori T. Higuchi S. Hayashida M. Ishii H. Esophageal cancer and aldehyde dehydrogenase-2 genotypes in Japanese males.Cancer Epidemiol. Biomarkers Prev. 1996; 5: 99-102PubMed Google Scholar, 24Cui R. Kamatani Y. Takahashi A. Usami M. Hosono N. Kawaguchi T. Tsunoda T. Kamatani N. Kubo M. Nakamura Y. Matsuda K. Functional variants in ADH1B and ALDH2 coupled with alcohol and smoking synergistically enhance esophageal cancer risk.Gastroenterology. 2009; 137: 1768-1775Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar To alleviate the" @default.
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• W2970978045 cites W1982698867 @default.
• W2970978045 cites W1983704379 @default.
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• W2970978045 cites W1987093439 @default.
• W2970978045 cites W1991356106 @default.
• W2970978045 cites W1991547675 @default.
• W2970978045 cites W1992220669 @default.
• W2970978045 cites W2000428499 @default.
• W2970978045 cites W2005910096 @default.
• W2970978045 cites W2007801750 @default.
• W2970978045 cites W2016521143 @default.
• W2970978045 cites W2024258467 @default.
• W2970978045 cites W2029617091 @default.
• W2970978045 cites W2051964656 @default.
• W2970978045 cites W2052640269 @default.
• W2970978045 cites W2057522312 @default.
• W2970978045 cites W2072540686 @default.
• W2970978045 cites W2072803013 @default.
• W2970978045 cites W2072832670 @default.
• W2970978045 cites W2078777307 @default.
• W2970978045 cites W2081659594 @default.
• W2970978045 cites W2084723599 @default.
• W2970978045 cites W2102141030 @default.
• W2970978045 cites W2107182659 @default.
• W2970978045 cites W2109996541 @default.
• W2970978045 cites W2110549318 @default.
• W2970978045 cites W2111329816 @default.
• W2970978045 cites W2119741858 @default.
• W2970978045 cites W2125386601 @default.
• W2970978045 cites W2137393689 @default.
• W2970978045 cites W2139207170 @default.
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