Drug discovery for hair cell regeneration in adult mammalian cochleae

描述（由申请人提供）：超过10%的人口听力受损。尽管哺乳动物耳蜗毛细胞（HC）的新生儿再生取得了重大进展，但成年人的再生已被证明是极其困难的。虽然γ分泌酶抑制剂在成年小鼠中再生噪声损伤的听觉HC方面显示出一定的前景，但没有药物被证明对成年人的听觉HC再生有效。有趣的是，我们最近证明，支持细胞（围绕毛细胞）可以通过两个关键基因的联合操作转化为成熟耳蜗中的毛细胞，其中一个（p27Kip1或p27）是失活的，其中一个（Atoh1）是激活的。这些发现使我们筛选p27的小分子抑制剂，并在细胞系中对其进行表征。我们建议测试这些铅化合物在耳蜗外植体和成年野生型和转基因小鼠体内的抑制作用，有或没有噪音损伤。这些探索性研究将为使用p27的小分子抑制剂以及Atoh1的小分子激活剂来再生成年哺乳动物中受损的听觉HC提供关键的“概念验证”。本文确定的最终先导化合物将进入药物开发管道进行优化，选择和临床前安全性分析，并最终进入人体HC再生的临床试验。这些研究可能会在治疗噪音、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.