Novel therapeutic for HPA hyperactivity

SummaryThe stress responsethough essential for survivalcan become dysregulatedresulting in diseaseHyperactivity of the hypothalamic pituitary adrenalHPAaxis characterizes a variety of illnesses including alcohol use disorderAUDdrug abusedepressionAlzheimer s and Parkinson s diseasesamong othersThis Phase I SBIR proposes a novel strategy aimed at normalizing pathologic HPA hyperactivityTherapeutic attempts to use glucocorticoid receptorGRantagonists have shown some promise in conditions like AUD and depressionHoweverchronically blocking GR mediated effects may be counterproductive asfor instanceit interferes with glucocorticoid negative feedbackleading to increased cortisol levels and mineralocorticoid receptor activationCRF receptor typeCRFantagonists have also been extensively exploredbut thus far have proven disappointingpossibly because of the pharmacodynamics pharmacokinetics properties of the existing drugsThereforethe identification of novel therapeutics to normalize hyperactivity of the HPA axis represents an area of significant unmet medical needHPA hyperactivity is characterized by higher production of corticotropin releasing factorCRFand glucocorticoidsProlonged exposure to elevated glucocorticoids has been proposed to act on the central nervous systemcausing hippocampal and prefrontal cortex functional impairmentsIn turnit is believed that reduced hippocampal inhibition of the hypothalamus further promotes HPA axis hyperactivityThe 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 AUDdepression and neurodegenerative diseases NarrativeStress is commonly experienced in daily lifeHoweverfrequent and chronic activation of the stress system can result in reduced resilience and predisposes to alcohol and drug abuse as well as a variety of illnessesThis Phase I SBIR proposal seeks to develop a novel therapeutic to reduce the detrimental consequences of hyperactivity of the hypothalamic pituitary adrenal axisHPAwhich characterizes a variety of illnesses including alcohol use disorderAUDdrug abusedepressionAlzheimer s and Parkinson s diseasesamong othersSpecificallythe present Phase I SBIR is focused on lead optimization and preclinical efficacy testing of a new therapeutic to normalize HPA axis hyperactivitywhich will lay the foundations for Investigational New DrugINDenabling studies in the eventual Phase II