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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要听力损失是我们社会的一个主要健康问题，影响着全球超过 3.6 亿人（世界卫生组织，2017 年）。氨基糖苷类化疗导致永久性听力损失 20-25%的接受治疗的患者。迄今为止，尚未有任何药物获得食品药品监督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正在进行的临床前试验与抗氧化剂、维生素和谷胱甘肽代谢有关，因此，许多这些化合物，例如硫代硫酸钠，可以干扰氨基糖苷类药物杀菌活性。我们对生物活性合成和天然化合物进行了高通量筛选使用斑马鱼作为氨基糖苷类耳毒性的平台并鉴定出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。我们的具体目标是测试这种天然化合物是否可以防止氨基糖苷类诱导的小鼠模型中全身给药造成的听力损失。我们的方法是腹腔内给药在用卡那霉素治疗的成年 C57BL/6 小鼠中使用该化合物 15 天，测量其 ABR 和 DPOAE 阈值、EP 并分析其耳蜗组织学。本品最大无毒剂量化合物将通过实验确定并测试其听力保护作用。这项工作将揭示了使用这种天然化合物来对抗氨基糖苷类诱导的听力损失。这项研究的结果将为开发新的治疗策略提供关键的原理证明对抗氨基糖苷类化疗的副作用。未来我们还将测试其功效这种化合物可以防止顺铂噪音和年龄相关的听力损失。如果成功的话，这该提案有可能成为治疗氨基糖苷类抗生素的重要一步导致患有严重革兰氏阴性细菌感染的患者听力损失。