ACSS2 inhibition in treating Alcohol Abuse

Alcohol use disorder represents a tremendous burden on society. While our understanding of neuronal pathways and circuitry involved in addiction has grown of late, efficacy of available treatments has not seen the same success. We uncovered a novel epigenetic process controlling neuronal plasticity that is key to long-term memory formation, involving the metabolic enzyme ACSS21. ACSS2 generates acetyl-CoA, a key cofactor for histone acetylation that is important for long-term memory2. We discovered that ACSS2 plays a critical role in alcohol-related learning by coordinating alcohol-induced histone acetylation and gene expression in the hippocampus, through conversion of alcohol-derived acetate to acetyl-CoA3. This new evidence further elucidates how ethanol may facilitate its rewarding properties via ACSS2-dependent histone acetylation. This radically new gene regulatory mechanism presents an attractive potential therapeutic strategy via pharmacological inhibition of ACSS2 to interfere with alcohol-related learning driving alcohol use disorder. In this proposal, we will test small molecule inhibitors of catalytic ACSS2 (ACSS2i) for use in animal models of alcohol use disorder (AUD). The proposed experiments will validate and establish ACSS2i as potential novel pharmacotherapies that may ultimately be used in the context of psychotherapy to treat alcohol use disorder.NARRATIVE Alcohol use disorder (AUD) is one of the most pervasive diseases in our society and conventional pharmacotherapeutics fail to counteract the tremendous social, psychological and financial burdens that this issue exacts on patients, families, and society. EpiVario will utilize our discovery of a novel epigenetic regulatory mechanism in neurons by inhibiting key metabolic enzyme ACSS2 to weaken drug-associated memory associations. EpiVario has generated 10 proprietary ACSS2 inhibitors, and the proposed SBIR grant will determine which compound is the most effective. By showing efficacy in industry-accepted preclinical animal models of AUD, we will address a critical unmet medical need.