Targeting AMP Deaminase 2 (AMPD2) to Metabolically Treat Alcohol Use Disorder and Liver Disease

About This Grant

Background and Innovation: Alcohol use disorder (AUD) accounts for over 88,000 deaths per year in the USA at a health care cost of 250 billion dollars each year. The issue of alcohol dependence and its deleterious consequences including liver disease is a particular burden for veterans, a population that continues experiencing long-standing issues with alcohol abuse. AUD is associated with addiction and behavioral disturbances as well as liver disease, pancreatitis and dementia and current treatments which include psychosocial support and medications are still suboptimal. One of the more prevalent and severe consequences of AUD is the development of liver disease and cirrhosis. Approximately 37% of veterans with cirrhosis had coexisting AUD. Based on these observations, we and others have proposed that treating AUD and ALD simultaneously will be a much better approach than each monotherapy alone. However, there is no treatment for ALD other than abstinence and current FDA-approved drugs for AUD offer variable results and have minimal or no direct effect on adiposity and liver disease. We have identified the purine degradation pathway (PDP) as the most prominent metabolic route preferentially activated in NAc, VTA and hepatocytes of ethanol-preferring (EP) mice as well as in ethanol-exposed human hepatocytes and neurons. The PDP is an enzymatic pathway that regulates energy balance by controlling intracellular levels of phosphonucleotides. It is initiated by the activation of 5’ adenosine monophosphate (AMP) Deaminase (AMPD) and results in the conversion of AMP into uric acid, a metabolite commonly found in liver and plasma of alcoholics. Our pilot data in mice indicate that the genetic or pharmacological blockade of the specific isoform of AMPD in liver and neurons, AMPD2, remarkably reduces consumption and preference of EP mice for ethanol while independently reverses ALD. Significance and Impact to Veterans Healthcare: Alcoholism is a serious problem among veterans, about 11% of veterans presenting for first-time care within the VA healthcare system meet the criteria for substance use disorder including cigarette smoking and consumption of alcohol. This is particularly relevant for young adults (18-25 years old) veterans compared to civilians. To date only three FDA approved medications in the U.S. are available for treatment of alcoholism (disulfiram, naltrexone, and acamprosate) and all show limited and variable responses, particularly among veterans in which discontinuation of these drugs is common when prescribed concurrently with other medications like statins or neuroleptics. Further, there are not specific treatments for alcohol-related deleterious consequences like alcoholic liver disease (ALD) and therefore, new, effective, and safe medications for the treatment of AUD and its consequences are desperately needed. Path to translation/implementation: The goal of this research is to perform proof-of-concept basic studies of the efficiency of targeting AMPD2 in ameliorating alcohol use disorder and alcoholic liver disease in mice. However, besides the genetic manipulations, we propose to conduct studies (Aim 1b) with specific AMPD inhibitors either alone or in combination with an FDA approved drug to prevent relapses in recovered alcoholics, naltrexone. These experiments which include identification of optimal dose (and its potential translation into human doses) as well as toxicity studies will provide good evidence about the potential druggability of this target for such a devastating condition like alcohol use disorder.