Mini-PCDH15 gene therapy rescues hearing in a mouse model of Usher syndrome type 1F.
Mini-PCDH15 gene therapy rescues hearing in a mouse model of Usher syndrome type 1F.
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DOI：
10.1038/s41467-023-38038-y
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发表时间：
2023-04-26
影响因子：
16.6
通讯作者：
Corey, David P.
中科院分区：
文献类型：
--
作者：
Ivanchenko, Maryna V.;Hathaway, Daniel M.;Klein, Alex J.;Pan, Bifeng;Strelkova, Olga;De-la-Torre, Pedro;Wu, Xudong;Peters, Cole W.;Mulhall, Eric M.;Booth, Kevin T.;Goldstein, Corey;Brower, Joseph;Sotomayor, Marcos;Indzhykulian, Artur A.;Corey, David P.
Usher综合征1型F （USH1F）是由原钙粘蛋白-15基因（PCDH15）突变引起的，以先天性耳聋、缺乏平衡和进行性失明为特征。在毛细胞（内耳的受体细胞）中，PCDH15是尖端连接的一个组成部分，尖端连接是打开机械感觉传导通道的细丝。由于PCDH15编码序列对于腺相关病毒（AAV）载体来说太大，因此对USH1F进行简单的基因添加治疗具有挑战性。我们使用合理的，基于结构的设计来设计微型pcdh15s，其中11个细胞外钙粘蛋白重复序列中的3-5被删除，但仍然结合伴侣蛋白。一些小型pcdh15可以安装在AAV中。将一种编码其中一种的AAV注射到USH1F小鼠模型的内耳中，产生一种迷你pcdh15，它能正确形成尖端连接，防止毛细胞束的退化，并挽救听力。mini - pcdh15可能是治疗USH1F耳聋的有效方法。PCDH15突变可导致Usher综合征1f的耳聋和失明，但由于PCDH15序列对于AAV载体来说太大，因此基因治疗很困难。在这里，作者设计了一种适合AAV的miniPCDH15，并挽救了小鼠Usher综合征1F模型的听力。
Usher syndrome type 1 F (USH1F), caused by mutations in the protocadherin-15 gene (PCDH15), is characterized by congenital deafness, lack of balance, and progressive blindness. In hair cells, the receptor cells of the inner ear, PCDH15 is a component of tip links, fine filaments which pull open mechanosensory transduction channels. A simple gene addition therapy for USH1F is challenging because the PCDH15 coding sequence is too large for adeno-associated virus (AAV) vectors. We use rational, structure-based design to engineer mini-PCDH15s in which 3–5 of the 11 extracellular cadherin repeats are deleted, but which still bind a partner protein. Some mini-PCDH15s can fit in an AAV. An AAV encoding one of these, injected into the inner ears of mouse models of USH1F, produces a mini-PCDH15 which properly forms tip links, prevents the degeneration of hair cell bundles, and rescues hearing. Mini-PCDH15s may be a useful therapy for the deafness of USH1F. Mutations in PCDH15 cause deafness and blindness in Usher syndrome 1 F, but gene therapy is difficult because the PCDH15 sequence is too large for AAV vectors. Here, the authors engineered a miniPCDH15 that fits in AAV and rescues hearing in mouse Usher syndrome 1F models.
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