Neonatal AAV gene therapy rescues hearing in a mouse model of SYNE4 deafness.
Neonatal AAV gene therapy rescues hearing in a mouse model of SYNE4 deafness.
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新生儿AAV基因治疗挽救了SYNE4耳聋小鼠的听力。
DOI：
10.15252/emmm.202013259
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发表时间：
2021-02-05
影响因子：
11.1
通讯作者：
Avraham KB
中科院分区：
文献类型：
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作者：
Taiber S;Cohen R;Yizhar-Barnea O;Sprinzak D;Holt JR;Avraham KB
遗传变异约占先天性和早发性耳聋病例的一半。在过去的十年中，用于将基因病毒递送到内耳中的方法和技术已经发展，使得基因治疗成为可行的和有吸引力的治疗方法。SYNE 4的变体，编码蛋白nesprin-4，核骨架和细胞骨架（LINC）连接器的成员，导致DFNB 76人类耳聋。Syne 4 −/−小鼠具有严重至极严重的进行性听力损失，并表现出毛细胞核定位错误和毛细胞变性。我们使用AAV 9-PHP.B（一种最近开发的合成腺相关病毒）将Syne 4的编码序列递送到新生Syne 4 −/−小鼠的内耳中。在这里，我们报告了毛细胞形态和存活的拯救，听觉功能的几乎完全恢复，以及听觉相关行为的恢复，没有观察到不良反应。关于治疗的持久性和人类干预的时间窗口仍然存在争议，但我们的研究结果表明，基因治疗有可能预防SYNE 4突变的人类听力损失。Syne 4缺乏会导致人类听力损失。在这项工作中，通过合成的AAV在Syne 4敲除小鼠中拯救了听觉功能，该AAV能够安全有效地转导耳蜗中的毛细胞。
Genetic variants account for approximately half the cases of congenital and early‐onset deafness. Methods and technologies for viral delivery of genes into the inner ear have evolved over the past decade to render gene therapy a viable and attractive approach for treatment. Variants in SYNE4, encoding the protein nesprin‐4, a member of the linker of nucleoskeleton and cytoskeleton (LINC), lead to DFNB76 human deafness. Syne4 −/− mice have severe‐to‐profound progressive hearing loss and exhibit mislocalization of hair cell nuclei and hair cell degeneration. We used AAV9‐PHP.B, a recently developed synthetic adeno‐associated virus, to deliver the coding sequence of Syne4 into the inner ears of neonatal Syne4 −/− mice. Here we report rescue of hair cell morphology and survival, nearly complete recovery of auditory function, and restoration of auditory‐associated behaviors, without observed adverse effects. Uncertainties remain regarding the durability of the treatment and the time window for intervention in humans, but our results suggest that gene therapy has the potential to prevent hearing loss in humans with SYNE4 mutations. Syne4 deficiency leads to hearing loss in humans. In this work, auditory function was rescued in Syne4 knockout mice by a synthetic AAV that enables safe and efficient transduction of hair cells in the cochlea.