Alcohol use disorder (AUD) represents a major medical and social burden worldwide and results in immense suffering for AUD patients and their families. A major goal of AUD research is the development and optimization of the use of effective drugs to treat this disorder. However, only a very small number of drugs? acamprosate, naltrexone and disulfiram?have received FDA approval for the treatment of AUD in the United States, and only a small proportion of alcoholic patients respond to treatment with these agents by achieving sustained abstinence. It would be a major achievement for Precision Medicine if we were to develop ways to better individualize the drug therapy of AUD patients in order to increase the frequency of the achievement of abstinence and to select the patients most likely to respond prior to the initiation of drug therapy. The studies of acamprosate proposed in this application will help to move us toward those goals and?by using acamprosate both as an approved therapeutic agent and as a ?molecular probe? for AUD--we will increase our understanding of acamprosate mechanism(s) of action and of the underlying pathophysiology of this disorder, thus helping make it possible to develop better and more effective drugs in the future. In Project 2, we will take advantage of our extensive experience and success in the application of metabolomics? particularly when joined with genomics and functional genomics, of our earlier acamprosate clinical trial performed with P20 funding and of the placebo-controlled acamprosate trial proposed with support from this application to apply ?pharmacometabolomics? and ?pharmacometabolomics-informed pharmacogenomics? to identify molecular and genomic signatures for acamprosate exposure and response in patients suffering from AUD. We should also emphasize that we propose to rapidly move ?beyond biomarkers? to functionally validate and mechanistically pursue the genes and pathways identified by using cell line-based model systems and neurons differentiated from iPS cells as well as animal models?studies that will be conducted in close collaboration with Projects 1 and 4. As described in Project 1, we will utilize sustained abstinence as our primary phenotype, but we will also take a similar approach to study additional phenotypes identified. RELEVANCE (See instructions): This innovative and comprehensive ?multiple omics? approach, based on the use of acamprosate as both a therapeutic agent and a molecular probe, will make it possible to identify molecular and genomic signatures for drug exposure and drug response while also advancing our understanding of drug action and of disease pathophysiology.
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