Adeno-associated virus-mediated gene transfer targeting normal and traumatized mouse utricle
Adeno-associated virus-mediated gene transfer targeting normal and traumatized mouse utricle
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DOI：
10.1038/gt.2014.73
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发表时间：
2014-08
期刊：
影响因子：
5.1
通讯作者：
Guopeng Wang;Jing-ying Guo;Zhe Peng;Yun Liu;Jing Xie;Shusheng Gong
中科院分区：
文献类型：
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作者：
Guopeng Wang;Jing-ying Guo;Zhe Peng;Yun Liu;Jing Xie;Shusheng Gong
平衡功能障碍与前庭毛细胞（HCs）的丧失密切相关。基因治疗在保护或再生前庭细胞以保持或恢复足够的前庭功能方面显示出前景。腺相关病毒（AAV）载体允许在没有毒性的情况下长期表达基因。为了无创地确定一种对前庭感觉上皮有利的AAV血清型，我们通过小管造口将AAV载体（血清型1、2、5、6和8）接种到成年小鼠小室中，对其转基因表达潜力进行了表征。结果表明，AAV8是最有效的AAV载体。游泳测试和听觉脑干反应的测量显示，导管造瘘后前庭功能和听力的最小损失。在AAV8输注后的正常胞室中，传导效率在第7天达到峰值，此后在前庭细胞中维持，在支持细胞（SCs）中维持3天。在链霉素损伤的胞室中，SC转导效率在第7天达到峰值，在第30天下降。综上所述，aav8介导的基因通过小管造口在小鼠前庭感觉上皮中进行高效、安全的转导，可能在未来成为人类前庭基因治疗的临床参考。
Balance dysfunction is closely associated with loss of vestibular hair cells (HCs). Gene therapy shows promise when used to protect or regenerate vestibular HCs to preserve or restore adequate vestibular function. Adeno-associated virus (AAV) vectors allow long-term gene expression in the absence of toxicity. To noninvasively define an AAV serotype exhibiting favorable tropism toward the vestibular sensory epithelium, we characterized the transgene expression potential of AAV vectors (serotypes 1, 2, 5, 6 and 8) inoculated into adult mouse utricle via canalostomy. We found that AAV8 was the most effective AAV vector in utricular gene transfer. Swim tests and measurements of auditory brainstem response revealed minimal loss of vestibular function and hearing after canalostomy. In the normal utricle after AAV8 infusion, transduction efficiency peaked at 7 days, and was maintained thereafter, in vestibular HCs, and at 3 days in supporting cells (SCs). In the streptomycin-lesioned utricle, the SC transduction efficiency peaked at 7 days and decreased at 30 days. In conclusion, AAV8-mediated gene transfer via canalostomy facilitates efficient and safe transduction in mouse vestibular sensory epithelium, and may in the future become clinically relevant for human vestibular gene therapy.