eiF2B Activators to Treat Noise-Induced Hearing Loss

eiF2B 激活剂治疗噪音引起的听力损失

• 批准号: 10482196
• 负责人: Malek Chouchane
• 金额: $ 30万
• 依托单位: JACARANDA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10482196
• 关键词: Acoustics; Acute; Address; Affect; American; Animal Model; Apoptosis; Auditory Brainstem Responses; Biological Assay; Biological Availability; Biological Sciences; Biology; Cell Death; Cells; Cellular biology; Chemicals; Chemistry; Chronic; Clinical; Cochlea; Data; Disease; Drug Design; Drug Kinetics; Drug Targeting; Endoplasmic Reticulum; Evaluation; Excretory function; Exposure to; Genetic; Goals; Government; Hair Cells; Hearing; Hearing Tests; Immunohistochemistry; In Vitro; Induction of Apoptosis; Injury; Intervention; Labyrinth; Metabolism; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Noise; Noise-Induced Hearing Loss; Occupational Exposure; Outcome Measure; Pathway interactions; Penetrance; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Physiology; Plasma; Property; Proteins; Public Health; Publishing; Regulation; Rodent; Safety; Secure; Series; Small Business Innovation Research Grant; Structure; Testing; TimeLine; Toxicology; Western Blotting; Work; absorption; arm; base; compound 30; dementia risk; disability-adjusted life years; dosage; drug development; efficacy study; efficacy testing; first-in-human; hearing impairment; hearing loss treatment; hearing range; hereditary hearing loss; in vivo; in vivo evaluation; inhibitor; innovation; insight; intraperitoneal; lead optimization; mouse model; noise exposure; novel; patient population; prevent; prevent hearing loss; public health relevance; response; sound; treatment trial

Abstract The overall goal of Jacaranda Biosciences, Inc. (JBI) is to develop compounds that will treat a broad range of hearing loss indications, a sorely unmet need. In this initial SBIR project, we will use our expertise in medicinal chemistry, cell biology and hearing physiology to functionally test and chemically optimize a series of novel compounds that modulate the unfolded protein response (UPR). These compounds, made and IP protected by JBI, will be used to demonstrate initial efficacy to prevent noise-induced hearing loss in our mouse model. Noise-induced hearing loss (NIHL) is a profound public health problem, affecting over 40 million Americans and causing the loss of 4 million disability-adjusted life years worldwide from occupational exposure annually. HL is also a significant risk factor for dementia, underscoring the expanded morbidity of this disorder. 27% of NIHL is from acute sound exposure, whereas 23% occurs from sub- acute or chronic exposure to sound, suggesting that interventions that target the mechanisms that underlie acute or sub-acute HL can make an immediate and transformative clinical impact for this large and inadequately treated patient population. Through our novel work in genetic and noise-induced animal models of hearing loss, we have discovered that homeostatic regulation of the UPR in the endoplasmic reticulum (ER) of cochlear hair cells is essential to prevent dysregulated over-activation of the UPR and subsequent hair cell death and hearing loss. Moreover, we have shown in published data that regulating the UPR through treatment with publicly available eiF2B activators and CHOP inhibitors (UPR pathway proteins) can prevent hair cell death and hearing loss in both noise-induced and genetic HL models. To take advantage of these insights, we will develop and optimize a proprietary series of novel eiF2B activators for eventual treatment in a large patient population. Our Aims are to (1) optimize the efficacy and physicochemical properties of our IP-protected, novel compounds; (2) Test whether the optimized compounds can lessen apoptosis and UPR over-activation in our cell-based models; and (3) determine whether these compounds prevent hearing loss and cochlear injury in our established animal model of acoustic overstimulation.

抽象的 JACARANDA BIOSCIENCES，INC。（JBI）的总体目标是开发可以对待广泛的化合物 听力损失指示范围，非常未满足的需求。在这个最初的SBIR项目中，我们将使用我们的 药物化学，细胞生物学和听力生理学方面的专业知识，可在功能上测试和 化学优化一系列调节展开蛋白质反应（UPR）的新型化合物。 这些由JBI保护和IP保护的化合物将用于证明初始功效 防止鼠标模型中噪声引起的听力损失。 噪声引起的听力损失（NIHL）是一个严重的公共卫生问题，影响超过4000万 美国人并导致全世界因职业而损失400万个残疾调整的生活年份 每年接触。 HL也是痴呆症的重要危险因素，强调了扩展 这种疾病的发病率。 27％的NIHL来自急性声音暴露，而23％来自子 - 急性或长期暴露于声音，表明针对机制的干预措施 急性或亚急性HL基础可以对此产生直接和变革的临床影响 大且经过足够的治疗患者人群。 通过我们在遗传和噪声引起的听力损失模型中的新工作，我们有 发现对耳蜗头发的内质网（ER）中UPR的体内平衡调节 细胞对于防止UPR的过度激活和随后的毛细胞死亡至关重要 和听力损失。此外，我们已经在已发布的数据中显示了通过 公开可用的EIF2B激活剂和CHOP抑制剂（UPR途径蛋白）的治疗可以 防止噪声引起的HL模型和遗传HL模型的毛细胞死亡和听力损失。服用 这些见解的优势，我们将开发和优化一系列专有的新型EIF2B 大量患者人群中最终治疗的激活剂。我们的目的是（1）优化 我们受ip的新型化合物的功效和物理化学特性； （2）测试是否 优化的化合物可以减少基于细胞的模型中的凋亡和UPR过度激活。和 （3）确定这些化合物是否阻止了我们已建立的 声学过度刺激的动物模型。