CNS Effects of Alcohol: Cellular Neurobiology

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Project Summary This request is for an administrative supplement to the Administrative Core of AA006420, The Scripps Research Institute’s Alcohol Research Center (TSRI-ARC), for $55,238 in direct costs. The purpose of this supplement request is to support data management, analysis, interpretation, and publication of results from the first completed hypocretin (orexin) antagonist study in humans with alcohol use disorder (AUD). Enrollment for this Phase 2a study was completed in Year 39 of the TSRI-ARC to meet a Specific Aim of the Clinical Component. Covid-related overnight staffing shortages for the inpatient component of the study at a collaborating institution necessitated extending subject enrollment through November 2022 to optimize study sample size by the end date of the grant on 12/31/22. The extended enrollment period only permitted cursory data entry, management, and analysis of top-line results to complete the final progress report for the grant and the posting of topline results on clinicaltrials.gov. Comprehensive analysis of results is critical for determining the direction of the pre-clinical hypocretin antagonist studies, including what parameters to measure in Year 40 of the TSRI-ARC Neuropharmacology Research Component, which has a primary focus on studying hypocretin in animal models of AUD. Funding for the clinical analyses was not included in the renewal application because there was no way to anticipate that the above circumstances would necessitate extending the enrollment period and preclude completion of data analysis within the proposed timeframe. Furthermore, we elected to sunset the Clinical Component in the renewal and any carryover funds from previous years have been expended, the Center budget was cut by 10%, and our indirect cost rate increased by 4% since the renewal was submitted. Thus, it is not possible to re-budget funds in the renewal to support the suvorexant human laboratory data analyses without significantly negatively impacting the Specific Aims of the renewal projects. However, part of Dr. Mason’s role as Director of the Administrative Core in Year 40 of the renewal is to facilitate the translation of basic research, including back translation from human studies, and these clinical data are critical to this aim. We understand it is unusual to request an administrative supplement in the first year of a funding cycle, but it is counterproductive to wait a year while the Neuropharmacology Component implements a research plan that may require modification based on information collected in the hypocretin antagonist clinical proof-of-concept study. This project has a high likelihood of exerting a sustained, powerful influence on the field by translating basic science findings into a novel neuroscience-based therapeutic strategy for AUD. Importantly, there is industry interest in moving this target forward as a treatment for AUD. If the requested funds are awarded, such translational goals can be met, and planned information will be available to guide the Neuropharmacology Component and the alcohol research community.