Gene Therapy Correction of Aldehyde Dehydrogenase 2 Deficiency
Gene Therapy Correction of Aldehyde Dehydrogenase 2 Deficiency
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DOI：
10.1016/j.omtm.2019.08.004
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发表时间：
2019-12-13
影响因子：
4.7
通讯作者：
Crystal, Ronald G.
中科院分区：
文献类型：
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作者：
Matsumura, Yuki;Stiles, Katie M.;Crystal, Ronald G.
乙醛脱氢酶2（ALDH 2）缺乏导致“亚洲潮红综合征”，表现为酒精引起的面部潮红，心动过速，恶心和头痛。最常见的遗传性酶缺乏症之一，影响35%-40%的东亚人和8%的世界人口。ALDH 2是乙醇代谢的关键酶，在乙醇攻击下，常见的ALDH 2 *2（E487 K）突变导致毒性乙醛的积累。ALDH 2 *2杂合子增加了患上消化道癌症的风险，并与吸烟和饮酒有关。我们假设一次性给予表达人ALDH 2编码序列的腺相关病毒（AAV）基因转移载体（AAVrh.10hALDH2）将纠正缺陷状态。将AAVrh.10hALDH2静脉内施用至Aldh 2敲除（Aldh 2（-/-））和Aldh 2 E487 K敲入纯合（Aldh 2 E487 K（+/+））小鼠。急性乙醇摄入后，未经治疗的ALDH 2缺陷小鼠的乙醛水平升高，在行为测试中表现不佳。相比之下，治疗的Aldh 2（-/-）和Aldh 2（E487 K +/+）小鼠具有较低的血清乙醛水平和改善的行为。因此，体内AAV介导的ALDH 2治疗可以逆转ALDH 2 *2个体的缺乏状态，消除亚洲潮红综合征并降低相关疾病的风险。
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 Aldh2(E487K+/+) 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.