Therapeutics to prevent aminoglycoside-induced hearing loss

预防氨基糖甙类药物引起的听力损失的治疗

• 批准号: 10081937
• 负责人: Marisa L. Zallocchi
• 金额: $ 24.23万
• 依托单位: TING THERAPEUTICS LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-17 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081937
• 关键词: Adjuvant; Adult; Affect; Alkaloids; Aminoglycosides; Animal Model; Animals; Antibiotics; Antidiabetic Drugs; Antifungal Agents; Antioxidants; Auditory Brainstem Responses; Auditory Threshold; Bacterial Infections; Blood - brain barrier anatomy; C57BL/6 Mouse; Capsicum; Cell Death; Cisplatin; Cochlea; Development; Disease; Diuretics; Dose; Embryo; Equilibrium; Fibroblasts; Future; Gentamicins; Glutathione Metabolism Pathway; Goals; Gram-Negative Bacterial Infections; Hair Cells; Health; Hearing; Hearing Tests; Histology; In Vitro; Infection; Inflammation; Jaborandi Pepper; Kanamycin; Light; Measures; Morphology; Mus; Natural Products; Neomycin; Noise; Organ of Corti; Patients; Pharmaceutical Preparations; Phase; Presbycusis; Prevention; Property; Quinoxalines; Societies; Stria Vascularis; Testing; Therapeutic; Time; Toxic effect; United States Food and Drug Administration; Work; World Health Organization; Zebrafish; aminoglycoside-induced ototoxicity; anti-cancer; anticancer activity; auditory threshold shift; bactericide; base; cancer therapy; cell injury; chemotherapy; cisplatin induced hearing loss; combat; cytotoxicity; drug candidate; efficacy testing; hearing impairment; high throughput screening; in vivo; in vivo Model; intraperitoneal; lateral line; mouse model; neuromast; novel therapeutics; otoacoustic emission; otoprotectant; permanent hearing loss; pre-clinical; preclinical trial; preservation; prevent; protective effect; side effect; small molecule libraries; sodium thiosulfate; spiral ganglion; subcutaneous; vitamin metabolism

PROJECT SUMMARY Hearing loss is a major health concern in our society, affecting over 360 million people worldwide (World Health Organization, 2017). Aminoglycoside chemotherapy causes permanent hearing loss in 20-25% of treated patients. To date, no drugs have been approved by the Food and Drug Administration for protection from aminoglycoside-related hearing loss. Most candidate compounds currently in pre-clinical trials are related to antioxidants, vitamins, and glutathione metabolism, and thus many of these compounds, such as sodium thiosulfate, can interfere with aminoglycoside bactericidal activity. We have conducted a high-throughput screen of bioactive synthetic and natural compounds employing zebrafish as our platform for aminoglycoside ototoxicity and identified a natural compound as an important therapeutic molecule for aminoglycoside-induced cell death and hearing loss. Our Specific Aim is to test whether this natural compound protects from aminoglycoside-induced hearing loss by systemic delivery in a mouse model. Our approach is to intraperitoneally administer the compound for 15 days in adult C57BL/6 mice treated with kanamycin, measure their ABR and DPOAEs thresholds, EPs and analyze their cochlear histology. The maximum non-toxic dose of this compound will be experimentally determined and tested for hearing-protective effects. This work will shed light on the possibility of using this natural compound to combat aminoglycoside-induced hearing loss. The results of this study will provide the key proof of principle to develop novel therapeutic strategies against side effects of aminoglycoside chemotherapy. In the future, we will also test the efficacy of this compound to protect against cisplatin- noise- and age-related hearing loss. If successful, this proposal, has the potential to be a significant step forward for the treatment of aminoglycoside- induced hearing loss in patients suffering from severe Gram-negative bacterial infections.

项目摘要 听力损失是我们社会的主要健康问题，全世界影响超过3.6亿人 （世界卫生组织，2017年）。氨基糖苷化疗导致永久性听力损失 20-25％的治疗患者。迄今为止，尚未获得食品和药物的批准 保护与氨基糖苷相关的听力损失的保护。大多数候选化合物 目前，临床前试验与抗氧化剂，维生素和谷胱甘肽代谢有关，以及 因此，许多这些化合物（例如硫代硫酸钠）都会干扰氨基糖苷 杀菌活性。 我们已经进行了生物活性合成和天然化合物的高通量屏幕 利用斑马鱼作为我们的氨基糖苷耳毒性的平台，并确定了天然化合物 作为氨基糖苷诱导的细胞死亡和听力丧失的重要治疗分子。 我们的具体目的是测试这种天然化合物是否可以保护氨基糖苷诱导的 在鼠标模型中全身传递的听力损失。我们的方法是腹膜内管理 成人C57BL/6小鼠用卡纳霉素治疗的化合物15天，测量其ABR和 DPOAES阈值，EPS和分析其人工耳蜗学。最大无毒剂量 化合物将经过实验确定并测试听力保护作用。这项工作将 阐明使用这种天然化合物对抗氨基糖苷诱导的可能性 听力损失。 这项研究的结果将为制定新型治疗策略提供原则的关键证明 反对氨基糖苷化学疗法的副作用。将来，我们还将测试 这种化合物可预防顺铂 - 噪声和年龄相关的听力损失。如果成功，这 提案有可能成为治疗氨基糖苷 - 患有严重革兰氏阴性细菌感染的患者的诱发听力损失。