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 potential. We 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 readouts. Our 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 encompass: (1) generation of a panel of multicolor hiPSC-derived neuronal and astrocyte cells with stable lineage specific fluorescent reporters; (2) execution of a phenotype-based pilot machine learning-enabled predictive abuse liability screen; and (3) combination of phenotypic profiling and gene expression analysis to characterize the molecular and cellular changes associated with compound exposure. Successful completion of our project will deliver 2 significant advances: (1) an important new technical framework to assess abuse potential of candidate therapeutics early in the development process and (2) an innovative, scalable in vitro assay platform that enables discovery of targets and associated candidate therapeutics to mitigate addiction phenotypes. These 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.
Public Health Relevance Statement: Project Narrative The ongoing opioid addiction crisis clearly evidences the need for new approaches to overcome addiction and mitigate the abuse liabilities of new therapies, yet a critical barrier to progress is the lack of in vitro assays in human cells to profile the abuse liabilities of therapeutics. Our project will deliver an innovative in vitro assay platform that enables 1) the assessment of abuse liability of candidate therapeutics early in development and 2) the discovery of targets and associated candidate therapeutics to prevent development of an addiction phenotype. These high impact advances align with government priorities such as the NIH HEAL (Helping to End Addiction Long-term) initiative and will deliver significant additional benefit to public health by enabling identification of safer new therapeutics without addictive potential.
NIH Spending Category: Biotechnology; Brain Disorders; Drug Abuse (NIDA only); Genetics; Machine Learning and Artificial Intelligence; Neurosciences; Opioid Misuse and Addiction; Opioids; Stem Cell Research; Stem Cell Research - Induced Pluripotent Stem Cell; Stem Cell Research - Induced Pluripotent Stem Cell - Human; Substance Abuse
Project Terms: addiction; Address; Analgesics; Astrocytes; base; Benchmarking; Biological Assay; Biological Markers; Biological Sciences; Cell Line; Cell Lineage; Cells; Classification; Data Analyses; design; Development; dopaminergic neuron; drug discovery; Drug Targeting; Economic Burden; Electrophysiology (science); Emergency Situation; Engineering; expression vector; Gene Expression; Gene Expression Alteration; Gene Expression Profiling; Gene Proteins; Generations; Glutamates; Government; Growth; healing; Human; In Vitro; in vitro Assay; in vitro Model; induced pluripotent stem cell; innovation; Machine Learning; Measurement; Measures; Methods; Microscopy; Modeling; Molecular; Molecular Profiling; mortality; multi-electrode arrays; Nervous system structure; Neurons; new therapeutic target; novel strategies; novel therapeutics; Opiate Addiction; opioid epidemic; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Physiology; Positioning Attribute; prevent; Process; programs; promoter; Property; Protein Array; protein expression; Proteomics; Public Health; Reporter; Specificity; stem; Structure; targeted biomarker; Technology; Testing; Therapeutic; therapeutic candidate; tool; transcriptome; transcriptome sequencing; Transfection; United States National Institutes of Health; Validation; vector
