Drug discovery for hair cell regeneration in adult mammalian cochleae

描述(申请人提供)：超过10%的人口听力受损。尽管在哺乳动物耳蜗毛细胞(HCS)的新生再生方面取得了重大进展，但事实证明，这种再生在成年动物中是极其困难的。虽然伽马分泌酶抑制剂在成年小鼠的噪音损伤的听觉HC再生方面显示出一些希望，但还没有药物被证明对成年人类的听觉HC再生有效。有趣的是，我们最近证明，在成熟的耳蜗中，通过联合操作两个关键基因，其中一个(p27Kip1或p27)被失活，而另一个(Atoh1)被激活，支持细胞(围绕毛细胞)可以转化为毛细胞。这些发现引导我们筛选p27的小分子抑制物，并在细胞系中对它们进行表征。我们建议在有或没有噪声损伤的成年野生型和转基因小鼠身上测试这些先导化合物在耳蜗外植体和体内的抑制效果。这些探索性研究将为使用p27的小分子抑制剂和Atoh1的小分子激活剂在成年哺乳动物体内再生受损的听觉HC提供关键的“概念证明”。这里确定的最终先导化合物将进入药物开发流水线，进行优化、筛选和临床前安全性分析，并最终进入人体HC再生的临床试验。这些研究可能导致在治疗由噪音、抗生素、化疗或年龄引起的听力损失方面取得突破。

DESCRIPTION (provided by applicant): Hearing is impaired in more than 10% of the human population. Despite significant progress in neonatal regeneration of mammalian cochlear hair cells (HCs), such regeneration in adults has proved extremely difficult. While gamma secretase inhibitors have shown some promise in regenerating noise-damaged auditory HCs in adult mice, no drugs have been proven effective for auditory HC regeneration in adult humans. Interestingly, we recently demonstrated that supporting cells (which surround hair cells) can be converted to HCs in mature cochleae through combined manipulation of two key genes, one of which (p27Kip1 or p27) is inactivated and one of which (Atoh1) is activated. These findings led us to screen for small-molecule inhibitors of p27 and to characterize them in cell lines. We propose to test the inhibitory effects of these lead compounds in cochlear explants and in vivo in adult wild-type and transgenic mice, with or without noise damage. These exploratory studies will provide the key "proof of concept" for using small-molecule inhibitors of p27, together with small-molecule activators of Atoh1, to regenerate damaged auditory HCs in adult mammals. The final lead compounds identified here will advance to the drug development pipeline for optimization, selection, and preclinical safety analysis, and eventually to clinical trials for HC regeneration in humans. These studies may lead to a breakthrough in the treatment of hearing loss caused by noise, antibiotics, chemotherapy, or age.