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中的一个主要健康问题，影响着全世界超过3.6亿人 （世界卫生组织，2017）。氨基糖苷类药物化疗导致永久性听力损失 20-25%的患者接受治疗。到目前为止，还没有药物被食品和药物管理局批准。 用于预防氨基糖苷类相关听力损失的给药。大多数候选化合物 目前在临床前试验中与抗氧化剂、维生素和谷胱甘肽代谢有关， 因此，许多这些化合物，如硫代硫酸钠，可以干扰氨基糖苷类， 杀菌活性 我们进行了高通量筛选生物活性合成和天然化合物 使用斑马鱼作为我们的氨基糖苷类耳毒性平台，并确定了一种天然化合物 作为氨基糖苷类诱导的细胞死亡和听力损失的重要治疗分子。 我们的具体目的是测试这种天然化合物是否能保护氨基糖苷类诱导的 在小鼠模型中通过全身递送的听力损失。我们的方法是腹腔注射 在用卡那霉素处理的成年C57 BL/6小鼠中，将化合物持续15天，测量它们的ABR， DPOAEs阈值、诱发电位及耳蜗组织学分析。最大无毒剂量 将通过实验确定并测试化合物的听力保护效果。这项工作将 阐明了使用这种天然化合物对抗氨基糖苷类诱导的 听力损失 本研究的结果将为开发新的治疗策略提供关键的原则证据 对抗氨基糖苷类化疗的副作用。未来，我们还将测试 这种化合物，以防止顺铂-噪音-和年龄相关的听力损失。如果成功，这 建议，有可能成为氨基糖苷类药物治疗的重要一步- 严重革兰氏阴性细菌感染患者的听力损失。