Drug Discovery for the Prevention of Hearing Loss

描述(申请人提供)：这项研究计划旨在测试候选药物的有效性，以保护内耳感受器细胞(毛细胞)丧失和系统治疗革兰氏阴性抗生素患者导致的听力损失。内耳毛细胞的丧失是听力丧失和平衡障碍的主要原因，影响到大约3100万美国人。正在研究的候选药物将是PR0T01的类似物，这是一种利用斑马鱼幼体侧线机械感觉毛细胞的良好特征的化学筛选在体内发现的小分子类药物化合物。PR0T01暴露可为斑马鱼毛细胞提供强大的保护，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。提出了以下具体目标。1)使用具有良好特性、稳健和灵敏的斑马鱼侧线毛细胞分析，筛选PR0T01的类似物，以获得对毛细胞和其他药物特性的优化保护。2)根据对新霉素引起的毛细胞丢失、庆大霉素引起的急性和慢性毛细胞丢失、通过MIC/MBL测试氨基糖苷作为抑菌剂的正常效果以及毛细胞对氨基糖苷的摄取的详细评估，使用二次测试来评估最有希望的新原药类似物以确定有前景的HITs中的先导化合物。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的定量评估，评估铅原类似物在成年大鼠体内针对氨基糖苷类药物引起的损伤提供听力保护的能力；4)与NIH支持的承包商合作，直接进行IND和I期临床制备铅化合物。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损伤的能力。在哺乳动物系统中优化先导化合物和验证将为未来在人类患者身上进行临床试验提供基本的药物开发信息。 与公共卫生相关：由于内耳细胞受伤或丧失而导致的听力和平衡障碍，影响着3000多万美国人和世界上近10亿人。主要原因之一是使用用于治疗传染病或癌症的药物治疗。这里提出的研究目标是开发在保持药用价值的同时预防听力损失的药物。

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.