A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear.
A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear.
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DOI：
10.1038/nbt.3781
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发表时间：
2017-03
影响因子：
46.9
通讯作者：
Vandenberghe LH
中科院分区：
文献类型：
--
作者：
Landegger LD;Pan B;Askew C;Wassmer SJ;Gluck SD;Galvin A;Taylor R;Forge A;Stankovic KM;Holt JR;Vandenberghe LH
开发听力损失基因疗法的努力受到缺乏安全，有效和临床相关的交付方式的阻碍。在这里，我们证明了Anc 80 L 65的安全性和有效性，一个合理设计的合成载体，转基因传递到小鼠耳蜗。用编码eGFP的Anc 80 L 65孵育的耳蜗外植体显示出内毛细胞和外毛细胞的高水平转导（60-100%）。通过圆窗膜注射Anc 80 L 65导致内毛细胞和外毛细胞的高效转导，这是对常规腺相关病毒（AAV）载体的实质性改进。Anc 80 L 65圆窗注射耐受性良好，如感觉细胞功能、听力和前庭功能以及免疫学参数所示。Anc 80 L 65以高速率靶向外毛细胞的能力，这是恢复复杂听觉功能的必要条件，可能使未来的基因疗法能够用于听力和平衡障碍。
Efforts to develop gene therapies for hearing loss have been hampered by the lack of safe, efficient, and clinically relevant delivery modalities. Here we demonstrate the safety and efficiency of Anc80L65, a rationally designed synthetic vector, for transgene delivery to the mouse cochlea. Cochlear explants incubated with Anc80L65 encoding eGFP demonstrated high level transduction of inner and outer hair cells (60–100%). Injection of Anc80L65 through the round window membrane resulted in highly efficient transduction of inner and outer hair cells, a substantial improvement over conventional adeno-associated virus (AAV) vectors. Anc80L65 round window injection was well tolerated, as indicated by sensory cell function, hearing and vestibular function, and immunologic parameters. The ability of Anc80L65 to target outer hair cells at high rates, a requirement for restoration of complex auditory function, may enable future gene therapies for hearing and balance disorders.