Liver-directed adeno-associated virus serotype 8 gene transfer rescues a lethal murine model of citrullinemia type 1
Liver-directed adeno-associated virus serotype 8 gene transfer rescues a lethal murine model of citrullinemia type 1
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DOI：
10.1038/gt.2013.53
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发表时间：
2013-12-01
期刊：
影响因子：
5.1
通讯作者：
McGuire, P. J.
中科院分区：
文献类型：
--
作者：
Chandler, R. J.;Tarasenko, T. N.;McGuire, P. J.
瓜氨酸血症1型（CTLN 1）是一种常染色体隐性遗传的代谢疾病，由维生素A琥珀酸合成酶缺乏引起。尽管有最佳的管理，CTLN 1患者仍然患有致命的代谢不稳定性，并经历危及生命的急性高氨血症发作。使用在生命的前21天内显示致死性的CTLN 1（倍数/倍数）的鼠模型来确定腺相关病毒（AAV）基因转移作为潜在疗法的功效。将AAV血清型8（AAV 8）载体工程化以在肝脏特异性启动子（甲状腺素结合球蛋白，TBG）的控制下表达人ASS 1 cDNA，AAV 8-TBG-hASS 1，并通过腹膜内注射递送至7-10日龄小鼠。超过95%的小鼠被从致死性中拯救出来，并且在接受单剂量的载体后存活期延长超过100天。AAV 8-TBG-hASS 7处理导致hASS 1的肝脏特异性表达、ASS 1酶活性增加、血浆氨和瓜氨酸浓度降低以及倍数/倍数生长和皮肤表型的显著表型改善。这些实验强调了使用AAV 8载体进行肝靶向基因治疗的基因转移方法，该方法可以作为CTLN 1的治疗方法。
Citrullinemia type 1 (CTLN1) is an autosomal recessive disorder of metabolism caused by a deficiency of argininosuccinate synthetase. Despite optimal management, CTLN1 patients still suffer from lethal metabolic instability and experience life-threatening episodes of acute hyperammonemia. A murine model of CTLN1 (fold/fold) that displays lethality within the first 21 days of life was used to determine the efficacy of adeno-associated viral (AAV) gene transfer as a potential therapy. An AAV serotype 8 (AAV8) vector was engineered to express the human ASS1 cDNA under the control of a liver-specific promoter (thyroxine-binding globulin, TBG), AAV8-TBG-hASS1, and delivered to 7-10 days old mice via intraperitoneal injection. Greater than 95% of the mice were rescued from lethality and survival was extended beyond 100 days after receiving a single dose of vector. AAV8-TBG-hASS7 treatment resulted in liver-specific expression of hASS1, increased ASS1 enzyme activity, reduction in plasma ammonia and citrulline concentrations and significant phenotypic improvement of the fold/fold growth and skin phenotypes. These experiments highlight a gene transfer approach using AAV8 vector for liver-targeted gene therapy that could serve as a treatment for CTLN1.