Rescue of Hearing by Gene Delivery to Inner-Ear Hair Cells Using Exosome-Associated AAV
Rescue of Hearing by Gene Delivery to Inner-Ear Hair Cells Using Exosome-Associated AAV
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DOI：
10.1016/j.ymthe.2016.12.010
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发表时间：
2017-02-01
影响因子：
12.4
通讯作者：
Maguire, Casey A.
中科院分区：
文献类型：
--
作者：
Gyorgy, Bence;Sage, Cyrille;Maguire, Casey A.
腺相关病毒（AAV）是一种安全有效的视网膜疾病基因治疗载体。听力障碍的基因治疗并不先进，部分原因是基因传递到内耳感觉毛细胞的效率低下。虽然AAV能传导小鼠耳蜗内毛细胞，但外毛细胞仍难以传导。在这里，我们证明了外泌体相关AAV （exo-AAV）载体是所有内耳毛细胞的转基因有效载体。ExoAAV1-GFP在体外培养小鼠耳蜗和在体内直接注射耳蜗中都比常规的AAV1-GFP更有效。通过听觉和前庭功能测试，Exo-AAV在体内无毒性。最后，exo-AAV1基因治疗部分恢复遗传性耳聋小鼠模型的听力（脂肪瘤HMGIC融合伴侣样5/毛细胞立体纤毛四跨膜蛋白[Lhfpl5/ Tmh(-/-)]）。Exo-AAV是一种强大的毛细胞研究基因传递系统，可用于耳聋的基因治疗。
Adeno-associated virus (AAV) is a safe and effective vector for gene therapy for retinal disorders. Gene therapy for hearing disorders is not as advanced, in part because gene delivery to sensory hair cells of the inner ear is inefficient. Although AAV transduces the inner hair cells of the mouse cochlea, outer hair cells remain refractory to transduction. Here, we demonstrate that a vector, exosome-associated AAV (exo-AAV), is a potent carrier of transgenes to all inner ear hair cells. ExoAAV1-GFP is more efficient than conventional AAV1-GFP, both in mouse cochlear explants in vitro and with direct cochlear injection in vivo. Exo-AAV shows no toxicity in vivo, as assayed by tests of auditory and vestibular function. Finally, exo-AAV1 gene therapy partially rescues hearing in a mouse model of hereditary deafness (lipoma HMGIC fusion partner-like 5/ tetraspan membrane protein of hair cell stereocilia [Lhfpl5/ Tmh(-/-)]). Exo-AAV is a powerful gene delivery system for hair cell research and may be useful for gene therapy for deafness.