High-throughput profiling of compound abuse liabilities and identification of addiction-related drug targets using an iPSC-enabled platform

Project Summary Abstract The scale of the US opioid addiction crisis clearly evidences the critical need for breakthroughs to assess compound abuse liabilities and to enable discovery of new analgesics with minimal abuse potentialWe hypothesize that altered addiction associated physiology can be modeled in co cultured hiPSC derived neuronal and astrocyte cells and detected by profiling gene expression alterations and associated phenotypic readoutsOur proposal addresses the significant lack of physiologically relevant tools capable of profiling relevant molecular changes that underpin addiction in the human nervous system by executing Specific Aims that encompassgeneration of a panel of multicolor hiPSC derived neuronal and astrocyte cells with stable lineage specific fluorescent reportersexecution of a phenotype based pilot machine learning enabled predictive abuse liability screenandcombination of phenotypic profiling and gene expression analysis to characterize the molecular and cellular changes associated with compound exposureSuccessful completion of our project will deliversignificant advancesan important new technical framework to assess abuse potential of candidate therapeutics early in the development process andan innovativescalable in vitro assay platform that enables discovery of targets and associated candidate therapeutics to mitigate addiction phenotypesThese innovations will position Cairn Biosciences to initiate drug discovery programs that will bring significant societal benefit by helping to stem the growth of the US opioid crisis and reduce the mortality rates and economic burden associated with this National Emergency Project Narrative The ongoing opioid addiction crisis clearly evidences the need for new approaches to overcome addiction and mitigate the abuse liabilities of new therapiesyet a critical barrier to progress is the lack of in vitro assays in human cells to profile the abuse liabilities of therapeuticsOur project will deliver an innovative in vitro assay platform that enablesthe assessment of abuse liability of candidate therapeutics early in development andthe discovery of targets and associated candidate therapeutics to prevent development of an addiction phenotypeThese high impact advances align with government priorities such as the NIH HEALHelping to End Addiction Long terminitiative and will deliver significant additional benefit to public health by enabling identification of safer new therapeutics without addictive potential