Drug Discovery for the Prevention of Hearing Loss

描述（由申请人提供）：本研究项目旨在测试候选药物的疗效，以防止因使用革兰氏阴性抗生素患者全身治疗而导致的内耳受体细胞（毛细胞）损失和听力损失。内耳毛细胞的损失是听力损失和平衡功能障碍的主要原因，影响了大约3100万美国人。正在研究的候选药物将是PR0T01的类似物，PR0T01是一种小分子药物样化合物，通过对斑马鱼幼虫体内侧线机械感觉毛细胞的化学筛选发现。PR0T01暴露为斑马鱼毛细胞提供了强大的保护，使其免受各种氨基糖苷类抗生素条件和暴露水平的影响，并在体外和体内保护啮齿动物内耳毛细胞。提出以下具体目标。1)使用特性良好、稳健且敏感的斑马鱼侧线毛细胞试验筛选PR0T01类似物，以获得对毛细胞的最佳保护和其他药物特性。2)基于对新霉素诱导的毛细胞损失、庆大霉素诱导的急性和慢性毛细胞损失的详细评估、MIC/MBL测试中氨基糖苷作为抗菌剂的正常疗效以及毛细胞对氨基糖苷的摄取，通过二级分析来评估最有希望的新PROTO类似物，以确定有希望的先导化合物。这些实验将继续利用斑马鱼幼体毛细胞平台。3)通过完善的听觉脑干反应（AER）测试和内耳毛细胞完整性定量评估，评估铅PROTO类似物在成熟大鼠体内对氨基糖苷诱导损伤的听力保护能力；4)与NIH支持的承包商合作，直接进行先导化合物的IND和I期临床制备。具体目标中概述的研究将重点分析PR0T01类似物保护毛细胞免受药物诱导损伤的能力。先导化合物的优化和在哺乳动物系统中的验证将为未来在人类患者中的临床试验提供必要的药物开发信息。

DESCRIPTION (provided by applicant): This research program is designed to test the efficacy of candidate drugs, for protection against inner ear receptor cell (hair cell) loss and hearing loss resulting from systemic treatment of patients with gram- negative antibiotics. Loss of inner ear hair cells is the leading cause of hearing loss and balance dysfunction, affecting approximately 31 million Americans. The candidate drugs under investigation will be analogs of PR0T01, a small molecule, drug-like compound discovered using a well-characterized chemical screen of lateral line mechanosensory hair cells of larval zebrafish, in vivo. PR0T01 exposure provides robust protection of zebrafish hair cells hair cells against a broad range of aminoglycoside antibiotic conditions and exposure levels, and protects rodent inner ear hair cells in vitro and in vivo. The following Specific aims are proposed. 1) Screen analogs of PR0T01 for those "hits" with optimized protection of hair cells and other drug characteristics using a well characterized, robust and sensitive zebrafish lateral line hair cell assay. 2) Evaluate the most promising new PROTO analogs with secondary assays to determine lead compounds from among promising hits, based on detailed assessment of neomycin-induced hair cell loss, acute and chronic gentamicin-induced hair cell loss, normal efficacy of aminoglycoside as a bacteriostatic agent via MIC/MBL tests, and uptake of the aminoglycoside by hair cells. These experiments will continue to utilize the larval zebrafish hair cell platform. 3) Evaluate lead PROTO analogs for their ability to confer hearing protection against aminoglycoside-induced damage in vivo in mature rats by testing with a well-established auditory brain stem response (AER) assay and by quantitative assessment of inner ear hair cell integrity, 4) Direct IND and phase I clinical preparation of lead compounds in conjunction with NIH supported contractors. The studies outlined in the specific aims will provide a focused analysis of the ability of PR0T01 analogs to protect hair cells from drug-induced damage. Optimization of lead compounds and validation in a mammalian system will provide essential drug development information for future clinical trials in human patients. PUBLIC HEALTH RELEVANCE: Hearing and balance disorders, due to injury or loss of the inner ear cells affects over 30 million Americans and almost a billion people in the world. One of the leading causes is treatment with medicinal drugs used for infectious diseases or cancer treatments. The goal of the research proposed here is to develop drugs that prevent the hearing loss, while preserving the medicinal benefits.