Therapeutics to prevent aminoglycoside-induced hearing loss

项目总结 听力损失是我们社会的一个主要健康问题，全世界有超过3.6亿人受到影响。 (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。到目前为止，还没有药物被食品和药物管理局批准 保护氨基糖苷类相关听力损失的管理。大多数候选化合物 目前处于临床前试验的是与抗氧化剂、维生素和谷胱甘肽代谢有关的物质，以及 因此，许多这样的化合物，如硫代硫酸钠，会干扰氨基糖苷类药物。 杀菌活性。 我们已经对具有生物活性的合成和天然化合物进行了高通量筛选 以斑马鱼为平台检测氨基糖苷类耳毒性并鉴定出一种天然化合物 作为治疗氨基糖苷类药物所致细胞死亡和听力损失的重要分子。 我们的具体目标是测试这种天然化合物是否能预防氨基糖苷类药物引起的 小鼠模型中全身给药导致的听力损失。我们的方法是通过腹膜腔给药 用卡那霉素给成年C57BL/6小鼠灌胃15天后，测定其ABR和 DPOAEs阈值、EPs，并分析其耳蜗组织学改变。本产品的最大无毒剂量 将对化合物进行实验测定和听力保护效果测试。这项工作将 阐明了使用这种天然化合物对抗氨基糖苷类药物的可能性 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则证据。 对抗氨基糖苷类化疗的副作用。在未来，我们还将测试 这种化合物可以防止顺铂引起的噪音和年龄相关性听力损失。如果成功，这将是 该提案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。

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.