Novel therapeutic for HPA hyperactivity

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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.