Unravelling drug-gene-phenotype interactions in complex cardiovascular diseases (iCASE)

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Globally, cardiovascular disease is the leading cause of death, with underlying genetic mutations, comorbidities and drug-induced off-target cardiotoxicity being especially troublesome. Inappropriate testing models belie these issues. The top 200 drugs account for 66.6% of the 4.3bn prescriptions in the USA/pa. Yet, 81 are black boxed, 82 carry cardiovascular adverse drug reaction warnings and 1 in 7 licensed drugs deemed efficacious in phase III trials are withdrawn from the market.This collaborative project is joint between Universities of Nottingham and Birmingham, AstraZeneca and GlaxoSmithKline. Collective interdisciplinary experience spans human induced pluripotent stem cells (hiPSCs), differentiation to cardiovascular linages, molecular/functional phenotyping, robotics, pharmacology, transcriptomics and bioinformatics/coding/AI. Our published work pioneered CRISPR gene editing in hiPSC to create variants that cause hypertrophic cardiomyopathy (HCM), a complex heterogeneous disease associated with considerable morbidity and mortality.Diverse skillsets and training will be combined to complete 3 objectives, aimed at future tailoring and translating drug therapy to patient genetics:- Establish baseline structure/functional readouts for healthy and diseased (hypertrophic cardiomyopathy; HCM) microtissues comprising cardiovascular lineages derived from human induced pluripotent stem cells (hiPSCs)- Quantify changes in microtissue structure/function challenged with patient-relevant drugs- Use omics/AI approaches for mechanistic insight and pathways information to refine drug use.