eiF2B Activators to Treat Noise-Induced Hearing Loss

摘要 雅卡兰达生物科学公司(JBI)的总体目标是开发能够治疗广泛疾病的化合物 一系列听力损失的迹象，这是一个严重的未得到满足的需求。在这个最初的SBIR项目中，我们将使用我们的 在药物化学、细胞生物学和听觉生理学方面的专业知识，以进行功能测试和 对一系列调节未折叠蛋白反应(UPR)的新型化合物进行化学优化。 这些化合物由JBI制造并受IP保护，将用于展示初步疗效 在我们的小鼠模型中防止噪音导致的听力损失。 噪声性听力损失是一个严重的公共卫生问题，影响着4000多万人 并导致全球因职业伤残调整后的生命年损失400万年 每年暴露在空气中。HL也是痴呆症的一个重要风险因素，强调了 这种疾病的发病率。27%的NIHL是由急性声音暴露引起的，而23%的NIHL发生于亚急性声音暴露 急性或慢性暴露于声音，表明针对以下机制的干预措施 潜在的急性或亚急性HL可对此产生直接和变革性的临床影响 患者数量多，治疗不充分。 通过我们在遗传和噪声诱导的听力损失动物模型方面的新工作，我们已经 发现耳蜗毛内质网中UPR的动态平衡调节 细胞对于防止UPR的异常过度激活和随后的毛细胞死亡至关重要 以及听力损失。此外，我们在已公布的数据中表明，通过 使用公开可用的eiF2B激活剂和CHOP抑制剂(UPR途径蛋白)治疗可以 在噪音诱导和遗传性HL模型中防止毛细胞死亡和听力损失。去拿 利用这些洞察力，我们将开发和优化一系列专有的新型eiF2B 激活剂，用于大规模患者的最终治疗。我们的目标是(1)优化 我们的受知识产权保护的新型化合物的有效性和物理化学性质；(2)测试是否 优化的化合物可以减少我们基于细胞的模型中的细胞凋亡和UPR过度激活； (3)确定这些化合物是否能预防听力损失和耳蜗损伤。 声学过度刺激的动物模型。

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.