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Gene therapy for cardiac disease

Hypertrophic cardiomyopathy (HCM), the most frequent cause of sudden death in young people, is a very common genetic disease of the heart. There are currently no known preventive or disease-modifying therapies for HCM. HCM is a monogenic hereditary disease with mutations in the sarcomeric genes MYH7 and MYBPC3 identified in 70% of variant-positive patients. CRISPR-Cas9 advances in genome editing have sparked excitement because it can solve genetic defects permanently, however, somatic non-dividing cells such as cardiomyocytes can only use the error-prone non-homologous end-joining (NHEJ) repair mechanism, and therefore template-based homology dependent repair, as performed in dividing cells, is not feasible.

Here we aim to develop a novel CRISPR/Cas9-based homology-independent targeted integration (HITI) strategy for cardiomyocytes in vivo, that is based on adeno-associated viral (AAV) delivery to genetically repair a hereditary human HCM mutation in a pre-clinical mouse model. Our promising preliminary results show that HITI strategy is feasible and capable of knocking-in a cassette into a sarcomeric gene in vivo. We devised a novel HITI strategy that is capable of completely correcting a common founder human HCM mutation in the sarcomeric gene MYBPC3 and will test our approach in a knock-in mouse model carrying this mutation.

The current proposal is aimed at correcting one common HCM mutation in Mybpc3. However, the novel approach developed here can be applied to correct most mutations in most genes responsible for HCM and other cardiomyopathies and can potentially be used to

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