Novel therapeutic for HPA hyperactivity

总结。 下丘脑-垂体-肾上腺(HPA)轴是控制 对压力的外周反应。虽然压力反应对生存是必不可少的，但它可以成为 监管不力。HPA的过度活动是包括饮酒在内的各种疾病的特征 精神障碍(澳元)。HPA过度活动的特征是促肾上腺皮质激素释放量较高。 因子(CRF)和糖皮质激素。 这项第二阶段SBIR旨在开发一种新的生物疗法，旨在使病理正常化 HPA多动症。目前，调节HPA轴的药物并不理想。治疗性的 使用糖皮质激素受体(GR)拮抗剂的尝试在以下情况下显示出了一些希望 AUD和抑郁症。然而，长期阻断GR介导的效应可能会适得其反。 例如，它会干扰糖皮质激素的负反馈，导致皮质醇水平升高 和盐皮质激素受体的激活。CRF受体1型(CRF1)拮抗剂已被 进行了广泛的探索，但到目前为止证明令人失望，可能是因为 现有药物的药代动力学和药效学特性。因此， 确定新的治疗方法来正常化HPA轴的过度活动代表了一个领域 巨大的未得到满足的医疗需求。 这项建议将优化在第一阶段SBIR中验证的铅，并建立稳定的细胞系 为最终的研究性新药(IND)--使能研究和 临床试验。总而言之，本项目将为临床开发一种 对AUD和其他以HPA轴为特征的疾病的一流治疗 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.