Drug Discovery for the Prevention of Hearing Loss

描述（由申请方提供）：本研究项目旨在检测候选药物的疗效，用于保护患者免受革兰氏阴性抗生素全身治疗引起的内耳感受器细胞（毛细胞）损失和听力损失。内耳毛细胞的丧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。研究中的候选药物将是PR 0 T01的类似物，PR 0 T01是一种小分子药物样化合物，使用体内斑马鱼幼虫侧线机械感觉毛细胞的良好表征的化学筛选发现。PR 0 T01暴露为斑马鱼毛细胞提供了针对广泛的氨基糖苷类抗生素条件和暴露水平的鲁棒保护，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)使用充分表征的、稳健的和灵敏的斑马鱼侧线毛细胞测定，筛选具有优化的毛细胞保护和其他药物特征的PR 0 T01类似物的那些“命中”。2)根据对新霉素诱导的毛细胞损失、急性和慢性庆大霉素诱导的毛细胞损失、通过MIC/MBL试验测定的氨基糖苷类抑菌剂的正常功效以及毛细胞对氨基糖苷类的摄取的详细评估，通过二次试验评价最有前途的新PROTO类似物，以确定有前途的命中物中的先导化合物。这些实验将继续利用斑马鱼幼鱼毛细胞平台。3)通过采用成熟的听觉脑干反应（AER）试验和内耳毛细胞完整性的定量评估，评价先导PROTO类似物在成年大鼠体内提供听力保护以防止氨基糖苷类诱导损伤的能力，4）与NIH支持的承包商联合进行先导化合物的直接IND和I期临床制备。具体目标中概述的研究将提供对PR 0 T01类似物保护毛细胞免受药物诱导损伤的能力的重点分析。先导化合物的优化和在哺乳动物系统中的验证将为未来人类患者的临床试验提供必要的药物开发信息。 公共卫生相关性：听力和平衡障碍，由于内耳细胞的损伤或损失影响超过3000万美国人和世界上近10亿人。主要原因之一是使用用于传染病或癌症治疗的药物进行治疗。这里提出的研究目标是开发预防听力损失的药物，同时保留药用价值。

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.