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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy
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Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy

机译：来自恒河猴的新型腺相关病毒作为人类基因治疗的载体

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Tissues from rhesus monkeys were screened by PCR for the presence of sequences homologous to known adeno-associated virus (AAV) serotypes 1-6. DNA spanning entire rep-cap ORFs from two novel AAVs, called AAV7 and AAV8, were isolated. Sequence comparisons among these and previously described AAVs revealed the greatest divergence in capsid proteins. AAV7 and AAV8 were not neutralized by heterologous antisera raised to the other serotypes. Neutralizing antibodies to AAV7 and AAV8 were rare in human serum and, when present, were low in activity. Vectors formed with capsids from AAV7 and AAV8 were generated by using rep and inverted terminal repeats (ITRs) from AAV2 and were compared with similarly constructed vectors made from capsids of AAV1, AAV2, and AAV5. Murine models of skeletal muscle and liver-directed gene transfer were used to evaluate relative vector performance. AAV7 vectors demonstrated efficiencies of transgene expression in skeletal muscle equivalent to that observed with AAV1, the most efficient known serotype for this application. In liver, transgene expression was 10- to 100-fold higher with AAV8 than observed with other serotypes. This improved efficiency correlated with increased persistence of vector DNA and higher number of transduced hepatocytes. The efficiency of AAV8 vector for liver-directed gene transfer of factor IX was not impacted by preimmunization with the other AAV serotypes. Vectors based on these novel, nonhuman primate AAVs should be considered for human gene therapy because of low reactivity to antibodies directed to human AAVs and because gene transfer efficiency in muscle was similar to that obtained with the best known serotype, whereas, in liver, gene transfer was substantially higher than previously described.
机译：通过PCR筛选恒河猴的组织中与已知腺相关病毒（AAV）血清型1-6同源的序列的存在。从两个称为AAV7和AAV8的新型AAV中分离出跨越整个rep-cap ORF的DNA。这些和先前描述的AAV之间的序列比较揭示了衣壳蛋白的最大差异。 AAV7和AAV8没有被其他血清型的异源抗血清中和。在人血清中很少有针对AAV7和AAV8的中和抗体，并且在存在时活性较低。使用来自AAV2的rep和反向末端重复序列（ITR）生成由AAV7和AAV8的衣壳形成的载体，并将其与由AAV1，AAV2和AAV5的衣壳制成的相似构建的载体进行比较。使用小鼠骨骼肌和肝定向基因转移模型来评估相对载体性能。 AAV7载体在骨骼肌中的转基因表达效率与AAV1（该应用最有效的血清型）所观察到的效率相当。在肝脏中，AAV8的转基因表达比其他血清型高10到100倍。这种提高的效率与载体DNA的持久性增加和转导的肝细胞数量增加有关。用其他AAV血清型进行预免疫不会影响AAV8载体对肝脏的IX因子基因转移的效率。基于这些新颖的非人类灵长类动物AAV的载体应考虑用于人类基因治疗，因为与针对人类AAVs的抗体的反应性低，并且由于肌肉中的基因转移效率与最知名的血清型相似，而在肝脏中，基因转移明显高于先前所述。

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