Novel therapeutic for HPA hyperactivity

摘要 下丘脑-垂体-肾上腺（HPA）轴是控制下丘脑-垂体-肾上腺（HPA）系统的关键神经内分泌系统。 对压力的周边反应虽然压力反应对生存至关重要，但它可以成为 失调下丘脑-垂体-肾上腺过度活跃是多种疾病的特征，包括饮酒 疾病（AUD）。HPA过度活跃的特征是促肾上腺皮质激素释放激素的产生增加， 因子（CRF）和糖皮质激素。 这项II期SBIR旨在开发一种新的生物治疗方法，旨在使病理性 下丘脑-垂体-肾上腺过度活跃。调节HPA轴的药物目前是次优的。治疗 使用糖皮质激素受体（GR）拮抗剂的尝试已经显示出在诸如以下病症中的一些希望 澳元与抑郁症然而，长期阻断GR介导的作用可能适得其反 例如，它会干扰糖皮质激素的负反馈，导致皮质醇水平升高 和盐皮质激素受体激活。CRF受体1型（CRF 1）拮抗剂已被 广泛探索，但到目前为止已经证明令人失望，可能是因为 现有药物的药代动力学和药效学特性。因此 鉴定使HPA轴活动过度正常化的新疗法代表了一个领域， 严重未满足的医疗需求。 该提案将优化在I期SBIR中验证的电极导线，并建立稳定的细胞系，用于 为最终的试验性新药（IND）启动研究生产材料，以及 临床试验总之，本项目将为临床开发一种 AUD的一流治疗药物，可能用于以HPA轴为特征的其他疾病 多动症。

Summary. The hypothalamic pituitary adrenal (HPA) axis is the key neuroendocrine system that controls peripheral responses to stress. While the stress response is essential for survival, it can become dysregulated. Hyperactivity of the HPA characterizes a variety of illnesses including alcohol use disorder (AUD). HPA hyperactivity is characterized by higher production of corticotropin-releasing factor (CRF) and glucocorticoids. This Phase II SBIR aims to develop a novel biologic therapeutic aimed at normalizing pathologic HPA hyperactivity. Medications to modulate the HPA axis are currently sub-optimal. Therapeutic attempts to use glucocorticoid receptor (GR) antagonists have shown some promise in conditions like AUD and depression. However, chronically blocking GR-mediated effects can be counterproductive as, for instance, it interferes with glucocorticoid negative feedback, leading to increased cortisol levels and mineralocorticoid receptor activation. CRF receptor type 1 (CRF1) antagonists have been extensively explored, but thus far have proven disappointing, possibly because of the pharmacokinetics and pharmacodynamics properties of the existing drugs. Therefore, the identification of novel therapeutics to normalize hyperactivity of the HPA axis represents an area of significant unmet medical need. This proposal will optimize a lead validated in the Phase I SBIR and establish a stable cell line for the production of material for the eventual Investigational New Drug (IND)-enabling studies and clinical trials. Altogether, the present project will lay the foundations for the clinical development of a first-in-class therapeutic for AUD and potentially for other conditions characterized by HPA axis hyperactivity.