Cochlear gene therapy with ancestral AAV in adult mice: complete transduction of inner hair cells without cochlear dysfunction.
Cochlear gene therapy with ancestral AAV in adult mice: complete transduction of inner hair cells without cochlear dysfunction.
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DOI：
10.1038/srep45524
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发表时间：
2017-04-03
影响因子：
4.6
通讯作者：
Liberman MC
中科院分区：
文献类型：
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作者：
Suzuki J;Hashimoto K;Xiao R;Vandenberghe LH;Liberman MC
使用病毒载体进行内耳基因治疗在治疗遗传性听力障碍方面正受到越来越多的关注。迄今为止，大多数动物研究都是通过圆窗膜将病毒悬液注射到新生儿耳中。在整个耳蜗中实现毛细胞或感觉神经元的转导已被证明是困难的，并且没有研究能够在维持正常耳蜗功能的同时有效地使成人耳朵中的感觉细胞再生。在这里，我们表明，第一次，成功转导的所有内毛细胞和大多数外毛细胞在成人耳蜗通过病毒注射到后半规管。我们使用了“设计者”AAV，AAV 2/Anc 80 L 65，其中主要衣壳蛋白近似于AAV 1、2、8和9的祖先序列状态。我们的注射也转导了约10%的螺旋神经节细胞和更大比例的卫星细胞。在前庭感觉上皮中，病毒转导了大量的毛细胞和几乎所有的支持细胞，沿着接近一半的前庭神经节细胞。我们的结论是，这种病毒载体和这种传递途径在耳蜗和前庭感觉器官的基因治疗应用中有很大的希望。
The use of viral vectors for inner ear gene therapy is receiving increased attention for treatment of genetic hearing disorders. Most animal studies to date have injected viral suspensions into neonatal ears, via the round window membrane. Achieving transduction of hair cells, or sensory neurons, throughout the cochlea has proven difficult, and no studies have been able to efficiently transduce sensory cells in adult ears while maintaining normal cochlear function. Here, we show, for the first time, successful transduction of all inner hair cells and the majority of outer hair cells in an adult cochlea via virus injection into the posterior semicircular canal. We used a “designer” AAV, AAV2/Anc80L65, in which the main capsid proteins approximate the ancestral sequence state of AAV1, 2, 8, and 9. Our injections also transduced ~10% of spiral ganglion cells and a much larger fraction of their satellite cells. In the vestibular sensory epithelia, the virus transduced large numbers of hair cells and virtually all the supporting cells, along with close to half of the vestibular ganglion cells. We conclude that this viral vector and this delivery route hold great promise for gene therapy applications in both cochlear and vestibular sense organs.