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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Adeno-associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo.
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Adeno-associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo.

机译：腺相关病毒基因修复在体内纠正了遗传性酪氨酸血症的小鼠模型。

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Adeno-associated virus (AAV) vectors are ideal for performing gene repair due to their ability to target multiple different genomic loci, low immunogenicity, capability to achieve targeted and stable expression through integration, and low mutagenic and oncogenic potential. However, many handicaps to gene repair therapy remain. Most notable is the low frequency of correction in vivo. To date, this frequency is too low to be of therapeutic value for any disease. To address this, a point-mutation-based mouse model of the metabolic disease hereditary tyrosinemia type I was used to test whether targeted AAV integration by homologous recombination could achieve high-level stable gene repair in vivo. Both neonatal and adult mice were treated with AAV serotypes 2 and 8 carrying a wild-type genomic sequence for repairing the mutated Fah (fumarylacetoacetate hydrolase) gene. Hepatic gene repair was quantified by immunohistochemistry and supported with reverse transcription polymerase chain reaction and serology for functional correction parameters. Successful gene repair was observed with both serotypes but was more efficient with AAV8. Correction frequencies of up to 10(-3) were achieved and highly reproducible within typical dose ranges. In this model, repaired hepatocytes have a selective growth advantage and are thus able to proliferate to efficiently repopulate mutant livers and cure the underlying metabolic disease. Conclusion: AAV-mediated gene repair is feasible in vivo and can functionally correct an appropriate selection-based metabolic liver disease in both adults and neonates.
机译：腺相关病毒（AAV）载体具有靶向多种不同基因组位点的能力，低免疫原性，通过整合实现靶向和稳定表达的能力以及低致突变和致癌潜力，因此是进行基因修复的理想选择。然而，基因修复治疗的许多障碍仍然存在。最值得注意的是体内校正的频率低。迄今为止，该频率太低，不足以对任何疾病都具有治疗价值。为了解决这个问题，使用了基于点突变的I型遗传性遗传性酪氨酸血症小鼠模型来测试通过同源重组进行的靶向AAV整合能否在体内实现高水平的稳定基因修复。新生小鼠和成年小鼠均接受带有野生型基因组序列的AAV血清型2和8进行修复，以修复突变​​的Fah（富马酰乙酰乙酸水解酶）基因。通过免疫组织化学对肝基因修复进行定量，并通过逆转录聚合酶链反应和血清学支持功能校正参数。两种血清型均观察到成功的基因修复，但使用AAV8更有效。校正频率高达10（-3），在典型剂量范围内可高度重现。在该模型中，修复的肝细胞具有选择性的生长优势，因此能够增殖以有效地重新填充突变肝脏并治愈潜在的代谢性疾病。结论：AAV介导的基因修复在体内是可行的，并且可以在功能上纠正成人和新生儿基于选择的适当代谢性肝病。

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