Novel therapeutic for HPA hyperactivity - Summary.
The stress response, though essential for survival, can become dysregulated, resulting in
disease. Hyperactivity of the hypothalamic pituitary adrenal (HPA) axis characterizes a variety
of illnesses including alcohol use disorder (AUD), drug abuse, depression, Alzheimer’s and
Parkinson’s diseases, among others. This Phase I SBIR proposes a novel strategy aimed at
normalizing pathologic HPA hyperactivity. Therapeutic attempts to use glucocorticoid receptor
(GR) antagonists have shown some promise in conditions like AUD and depression. However,
chronically blocking GR-mediated effects may 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 also been
extensively explored, but thus far have proven disappointing, possibly because of the
pharmacodynamics/pharmacokinetics 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. HPA hyperactivity is characterized by higher
production of corticotropin-releasing factor (CRF) and glucocorticoids. Prolonged exposure to
elevated glucocorticoids has been proposed to act on the central nervous system, causing
hippocampal and prefrontal cortex functional impairments. In turn, it is believed that reduced
hippocampal inhibition of the hypothalamus further promotes HPA axis hyperactivity. The
present project will lay the foundations for the clinical development of a first-in-class
therapeutic for multiple conditions characterized by HPA axis hyperactivity including AUD,
depression and neurodegenerative diseases.
