Targeted Allele Suppression Prevents Progressive Hearing Loss in the Mature Murine Model of Human TMC1 Deafness
Targeted Allele Suppression Prevents Progressive Hearing Loss in the Mature Murine Model of Human TMC1 Deafness
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DOI：
10.1016/j.ymthe.2018.12.014
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发表时间：
2019-03-06
影响因子：
12.4
通讯作者：
Smith, Richard J. H.
中科院分区：
文献类型：
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作者：
Yoshimura, Hidekane;Shibata, Seiji B.;Smith, Richard J. H.
听力损失是人类最常见的感觉缺陷。它的纠正一直是几个基于基因治疗的研究探索各种干预措施的目标。尽管这些研究报告了不同程度的成功，但所有治疗都针对新生小鼠的内耳发育，这是人类胎龄26周之前耳蜗结构成熟的时间点。目前尚不清楚耳蜗基因治疗是否可以挽救成熟Corti器官的听力。在此，我们报告了第一项研究，以测试基因治疗的成年小鼠模型的人类耳聋。使用单个耳蜗内注射的人工microRNA携带的AAV载体，我们表明，RNAi介导的基因沉默可以减缓听力损失的进展，提高内毛细胞的存活，并防止静纤毛束变性在成熟的贝多芬小鼠，一个模型的人TMC 1耳聋。在成熟鼠耳中研究基因治疗的能力是将其转化为人类受试者的重要一步。
Hearing loss is the most common human sensory deficit. Its correction has been the goal of several gene-therapy based studies exploring a variety of interventions. Although these studies report varying degrees of success, all treatments have targeted developing inner ears in neonatal mice, a time point in the structural maturation of the cochlea prior to 26 weeks gestational age in humans. It is unclear whether cochlear gene therapy can salvage hearing in the mature organ of Corti. Herein, we report the first study to test gene therapy in an adult murine model of human deafness. Using a single intracochlear injection of an artificial microRNA carried in an AAV vector, we show that RNAi-mediated gene silencing can slow progression of hearing loss, improve inner hair cell survival, and prevent stereocilia bundle degeneration in the mature Beethoven mouse, a model of human TMC1 deafness. The ability to study gene therapy in mature murine ears constitutes a significant step toward its translation to human subjects.