Developing CRISPR-based therapies for hypertrophic cardiomyopathy using human cardiomyocytes in a dish

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Hypertrophic cardiomyopathy (HCM) is a common genetic disease of the cardiac muscle, predicted to affect approximately 1 in 500 worldwide. Most existing treatments seek to ameliorate symptoms, rather than addressing the underlying disease pathomechanisms. The aim of this project is to use cardiomyocytes derived from human stem cells (iPSC-CMs) as a model system to study genetic variants associated with HCM and develop curative genetic therapies. The focus of this project is to develop novel gene editing strategies based on the CRISPR-Cas platform to correct the genetic pathomechanisms that drive HCM, with the aim of comprehensively restoring healthy contractile function in the affected cardiomyocytes of the heart and reversing the HCM phenotype. This work will also evaluate novel technologies to deliver CRISPR-Cas editing machinery to cardiomyocytes. Alongside testing gene editing strategies, the iPSC-CM platform will be used to evaluate the pathogenicity of previously-uncharacterised genetic variants associated with HCM, and to improve our understanding of the mechanisms that drive HCM. Working with iPSC-CMs requires training in cell culture, basic molecular biology techniques and fluorescence microscopy. Generating cell lines for studying novel genetic variants requires training in the use of CRISPR-Cas9 for gene editing. Developing and evaluating genetic therapies will require additional training in bioinformatics and transcriptomics to design editing strategies and assess their efficacy. This project will also utilise 3D iPSC-CM-based models in an attempt to model disease in a cardiac tissue more akin to the adult myocardium found in human hearts. This will require training in the development of human cardiac organoids and engineered heart tissues.