AAV-S: A versatile capsid variant for transduction of mouse and primate inner ear.
AAV-S: A versatile capsid variant for transduction of mouse and primate inner ear.
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DOI：
10.1016/j.omtm.2021.03.019
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发表时间：
2021-06-11
期刊：
影响因子：
--
通讯作者：
Corey DP
中科院分区：
文献类型：
--
作者：
Ivanchenko MV;Hanlon KS;Hathaway DM;Klein AJ;Peters CW;Li Y;Tamvakologos PI;Nammour J;Maguire CA;Corey DP
使用腺相关病毒（AAV）载体治疗遗传性耳聋的基因治疗策略在一些小鼠听力损失模型中显示出显著的疗效。即便如此，很少有AAV衣壳能够同时覆盖内毛细胞和外毛细胞--这些细胞表达大多数耳聋基因--而在灵长类动物中，更少的衣壳能够有效地覆盖毛细胞。大多数临床试验将需要具有灵长类耳蜗中的内毛细胞和外毛细胞的稳健转导的AAV衣壳。在这里，我们测试了我们先前从随机衣壳文库AAV-S中分离的衣壳在小鼠和非人灵长类动物内耳中的转导。在小鼠和食蟹猴中，AAV-S在多种耳蜗细胞中介导高效的报告基因表达，包括内毛细胞和外毛细胞、纤维细胞和支持细胞。在Usher综合征3A型小鼠模型中，编码CLRN 1的AAV-S稳健且持久地挽救听力。总的来说，我们的数据表明，AAV-S是一个有前途的候选人治疗基因传递到人内耳。耳聋基因治疗的进展需要验证AAV衣壳在小鼠和非人灵长类动物耳蜗中的转基因递送，但只有一个存在。Ivanchenko及其同事证明，一种新的衣壳AAV-S可转导两种物种耳蜗中的临床相关细胞，并介导耳聋小鼠听力的稳健拯救。
Gene therapy strategies using adeno-associated virus (AAV) vectors to treat hereditary deafnesses have shown remarkable efficacy in some mouse models of hearing loss. Even so, there are few AAV capsids that transduce both inner and outer hair cells—the cells that express most deafness genes—and fewer still shown to transduce hair cells efficiently in primates. AAV capsids with robust transduction of inner and outer hair cells in primate cochlea will be needed for most clinical trials. Here, we test a capsid that we previously isolated from a random capsid library, AAV-S, for transduction in mouse and non-human primate inner ear. In both mice and cynomolgus macaques, AAV-S mediates highly efficient reporter gene expression in a variety of cochlear cells, including inner and outer hair cells, fibrocytes, and supporting cells. In a mouse model of Usher syndrome type 3A, AAV-S encoding CLRN1 robustly and durably rescues hearing. Overall, our data indicate that AAV-S is a promising candidate for therapeutic gene delivery to the human inner ear. Progress toward gene therapy for deafness requires AAV capsids validated for transgene delivery in mouse and non-human primate cochleas, but just one exists. Ivanchenko and colleagues demonstrate that a new capsid, AAV-S, transduces clinically relevant cells in cochleas of both species and mediates robust rescue of hearing in deaf mice.
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