Development of novel pharmacotherapies for AUD

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Project Summary The overall goal of this proposal is to characterize a lead compound with a novel mode of action (MOA) that reduces both stress- and dependence-related alcohol drinking in a preclinical model of Alcohol Use Disorder (AUD). AUD is a major problem in the U.S. as approximately 13.9% of adults meet AUD criteria per year. The annual economic burden of AUD is estimated at >$200 billion and AUD is a leading cause of preventable deaths in the USA. Persistent alcohol abuse and dependence is difficult to treat in part because alcohol increases the reactivity of the body’s stress systems. The influence of stress systems facilitates the “the dark side of addiction”, and stress is a primary factor that triggers relapse. Therefore, pharmacotherapies that can reduce stress- and dependence-associated alcohol drinking could reduce both heavy drinking and stress-triggered relapse in individuals suffering from AUD. We recently discovered that systemic administration of an epigenetic enzyme inhibitor reduced both stress- and dependence-potentiated alcohol drinking in a preclinical model. We have filed for patent protection of this entirely novel MOA to treat AUD, which provides a commercial path forward. In this Phase I STTR application, we will evaluate oral bioavailability of our lead compound to examine whether the preferred oral method of delivery is feasible for AUD treatment. We will also examine maximum tolerated dose (MTD) and behavioral toxicity measures. We will then determine optimal dosing conditions, and we seek to establish strong proof-of-principle data that these compounds reduce dependence- and stress-related alcohol drinking in multiple preclinical models and multiple mouse strains in both male and female mice. At the conclusion of these aims, we expect to have sufficient pre-clinical information for subsequent Phase II STTR studies targeting a future Investigational New Drug (IND) application.