Drug Discovery for the Prevention of Hearing Loss

预防听力损失的药物发现

• 批准号: 8128231
• 负责人: David W Raible
• 金额: $ 24.26万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8128231
• 关键词: Acute; Affect; Age Factors; Aging; American; Aminoglycoside Antibiotics; Aminoglycosides; Animals; Anti-Bacterial Agents; Antibiotics; Auditory; Biological Assay; Cells; Characteristics; Chemicals; Chronic; Cisplatin; Clinical; Clinical Trials; Communicable Diseases; Consultations; Contractor; Development; Drug Kinetics; Drug usage; Ear; Environmental Risk Factor; Epithelium; Equilibrium; Essential Drugs; Evoked Potentials, Auditory, Brain Stem; Functional disorder; Future; Gentamicins; Goals; Habilitation; Hair Cells; Health; Hearing; Hearing Tests; Hearing problem; Histocytochemistry; Human; In Vitro; Injury; Investigation; Investigational Drugs; Labyrinth; Lead; Measures; Neomycin; Patients; Performance; Pharmaceutical Preparations; Phase; Platinum; Preparation; Prevention; Principal Investigator; Property; Publishing; Rattus; Receptor Cell; Research; Rodent; Screening procedure; Sensory; System; Testing; Therapeutic; Therapeutic Agents; United States National Institutes of Health; Validation; Zebrafish; analog; base; cancer therapy; cell injury; design; drug candidate; drug development; drug discovery; efficacy testing; equilibration disorder; hearing impairment; in vivo; lateral line; neoplastic; pre-clinical; prevent; programs; research clinical testing; research study; small molecule; small molecule libraries; uptake

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.

描述（由申请人提供）：该研究计划旨在测试候选药物的功效，以防止内耳受体细胞（毛细胞）损失和由全身治疗革兰氏阴性抗生素患者的全身治疗导致的听力损失。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，类似于药物的化合物，使用了体内幼虫斑马鱼的侧向线机械感力细胞的特征化学筛选，体内。 PR0T01暴露可为斑马鱼毛细胞毛细胞提供强大的保护，以防止广泛的氨基糖苷抗生素条件和暴露水平，并在体外和体内保护啮齿动物的内耳毛细胞。提出了以下特定目标。 1）使用良好的，稳健和敏感的斑马鱼侧线毛细胞测定法，对毛细胞和其他药物特征进行优化的毛细胞和其他药物特征的“命中”的屏幕类似物。 2）基于对新霉素诱导的毛细胞损失，急性和慢性甲状腺素诱导的毛细胞损失，氨基糖苷的正常效率，通过麦克雷抑制剂作为菌培剂，通过MIC/mbl testss和amiNCtake和amINCTAKE and amINC，评估有前途的打击中最有希望的新的原始类似物，以确定有前途的效果中的铅化合物，以详细评估新霉素诱导的毛细胞损失，急性和慢性甲状腺素诱导的毛发细胞损失，正常的氨基糖苷效果，通过麦克雷抑制剂作为麦克雷抑制剂作为麦克雷抑制剂通过麦克雷剂/mbl firake和ambbl tests和amigyctake and amInigyc。这些实验将继续利用幼虫斑马鱼毛细胞平台。 3）评估铅原始类似物的能力，可以通过对成熟的听觉脑干反应（AER）测定和内耳毛细胞完整性进行定量评估，对成熟大鼠的氨基糖苷诱导的成熟大鼠的损伤，4）直接IND IND和I型IND和相位I型铅IniH铅的临床制备。特定目的中概述的研究将对PR0T01类似物保护毛细胞免受药物诱导的损伤的能力进行重点分析。哺乳动物系统中铅化合物和验证的优化将为人类患者的未来临床试验提供重要的药物开发信息。 公共卫生相关性：由于内耳细胞的伤害或丧失，听力和平衡疾病会影响超过3000万美国人，而世界上近十亿人则影响。主要原因之一是用用于传染病或癌症治疗的药物治疗。这里提出的研究的目的是开发可防止听力损失的药物，同时保留药物益处。