Recombinant Adeno-Associated Virus-mediated rescue of function in a mouse model of Dopamine Transporter Deficiency Syndrome
Recombinant Adeno-Associated Virus-mediated rescue of function in a mouse model of Dopamine Transporter Deficiency Syndrome
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DOI：
10.1038/srep46280
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发表时间：
2017-04-18
影响因子：
4.6
通讯作者：
Gainetdinov, R. R.
中科院分区：
文献类型：
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作者：
Illiano, P.;Bass, C. E.;Gainetdinov, R. R.
多巴胺转运蛋白缺乏综合征（Dopamine Transporter Deficiency Syndrome，DTDS）是一种罕见的常染色体隐性遗传疾病，由多巴胺转运蛋白（DAT）基因功能缺失突变引起，可导致儿童和成人严重的神经功能障碍。DAT-敲除（DAT-KO）小鼠是目前用于该综合征的最佳动物模型，其表现出功能性多巴胺能亢进和神经退行性表型，导致约36%的群体过早死亡。我们使用DAT-KO小鼠作为DTDS的模型，以探索一种新的组合腺相关病毒（AAV）基因治疗的潜在效用，通过选择性地在DA神经元和末梢中表达DAT，从而拯救异常的纹状体DA动力学，逆转特征性表型和行为异常，并预防过早死亡。这些数据表明，一种新的组合基因治疗的疗效，旨在挽救DA功能和相关的表型在小鼠模型中，最接近DAT缺陷中发现的DTDS。
Dopamine Transporter Deficiency Syndrome (DTDS) is a rare autosomal recessive disorder caused by loss-of-function mutations in dopamine transporter (DAT) gene, leading to severe neurological disabilities in children and adults. DAT-Knockout (DAT-KO) mouse is currently the best animal model for this syndrome, displaying functional hyperdopaminergia and neurodegenerative phenotype leading to premature death in similar to 36% of the population. We used DAT-KO mouse as model for DTDS to explore the potential utility of a novel combinatorial adeno-associated viral (AAV) gene therapy by expressing DAT selectively in DA neurons and terminals, resulting in the rescue of aberrant striatal DA dynamics, reversal of characteristic phenotypic and behavioral abnormalities, and prevention of premature death. These data indicate the efficacy of a new combinatorial gene therapy aimed at rescuing DA function and related phenotype in a mouse model that best approximates DAT deficiency found in DTDS.