György Bence, Sage Cyrille, Indzhykulian Artur A, Scheffer Deborah I, Brisson Alain R, Tan Sisareuth, Wu Xudong, Volak Adrienn, Mu Dakai, Tamvakologos Panos I, Li Yaqiao, Fitzpatrick Zachary, Ericsson Maria, Breakefield Xandra O, Corey David P, Maguire Casey A
Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA; Department of Neurology, Massachusetts General Hospital and NeuroDiscovery Center, Harvard Medical School, Building 149, Charlestown, Boston, MA 02129, USA.
Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
Mol Ther. 2017 Feb 1;25(2):379-391. doi: 10.1016/j.ymthe.2016.12.010. Epub 2017 Jan 9.
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. Exo-AAV1-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/Tmhs]). Exo-AAV is a powerful gene delivery system for hair cell research and may be useful for gene therapy for deafness.
腺相关病毒（AAV）是用于视网膜疾病基因治疗的一种安全有效的载体。听力障碍的基因治疗进展相对较慢，部分原因是向内耳感觉毛细胞的基因递送效率低下。尽管AAV可转导小鼠耳蜗的内毛细胞，但外毛细胞仍难以被转导。在此，我们证明一种载体，即外泌体相关AAV（exo-AAV），是向所有内耳毛细胞递送转基因的有效载体。在体外小鼠耳蜗外植体以及体内直接耳蜗注射中，Exo-AAV1-GFP都比传统的AAV1-GFP更有效。通过听觉和前庭功能测试分析，Exo-AAV在体内无毒性。最后，Exo-AAV1基因治疗在遗传性耳聋小鼠模型（脂肪瘤HMGIC融合伴侣样5/毛细胞静纤毛四跨膜蛋白[Lhfpl5/Tmhs]）中部分恢复了听力。Exo-AAV是用于毛细胞研究的强大基因递送系统，可能对耳聋的基因治疗有用。
