Alcohol Use Disorder: Acamprosate Pharmacometabolomics-informed Pharmacogenomics

PROJECT SUMMARY/ABSTRACT Acamprosate and naltrexone are major medications used in the treatment of alcohol use disorder (AUD). However, response to treatment with these drugs is variable, with only ~50% of patients achieving optimal outcomes. As a result, it would be important to identify molecular mechanisms underlying individual variation in

AUD drug treatment outcomes. That information could potentially facilitate the development of individualized AUD pharmacotherapy regimens as well as the development of novel AUD therapeutic agents. During the current funding cycle, we performed a series of “Pharmaco-Omic” studies designed to identify biomarkers

associated with acamprosate response for AUD patients enrolled in our Mayo Clinic Center for Individualized Treatment of Alcohol Dependence (CITA) clinical trial—one of the largest acamprosate AUD clinical trials and one for which we have generated a series of multiple omics datasets. Using those data, we identified

novel biomarkers associated with variation in acamprosate treatment outcomes. Those biomarkers included, for example, the FNDC4 gene and a series of other genes—genes which we now propose to study further by performing functional studies of the AUD biomarkers that we have already identified and to extend those studies

to include a series of protein biomarkers for both AUD drug response and AUD pathophysiology. Finally, we will also expand our studies to include the application of iPSC-derived brain organoids from both our AUD patients and control subjects to make it possible to identify genes and biological pathways that

contribute to acamprosate and naltrexone treatment response. In summary, the studies proposed in this application represent a systematic attempt to identify and study molecular mechanisms underlying and associated with variation in AUD drug treatment response phenotypes and AUD clinical outcomes in response to drug therapy. Our use of “multiple omics” to study samples from AUD patients treated with these

drugs, followed by “functional omic” studies of those samples and concluding with the generation and study of patient-derived brain organoids generated from the same patients make this series of studies truly unique and—based on our preliminary data—highly promising for the identification of novel candidate genes and

pathways. The results of the proposed studies would represent a significant step toward greater understanding of the biology of acamprosate and naltrexone treatment response in AUD, potentially leading to the development of better and more effective AUD drug therapy, an outcome that would represent a significant advance in the

treatment of this disorder.