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Hypertrophic Cardiomyopathy Mutation Reversed in Human Cell Line, Mouse Model With Gene Editing

In Nature Medicine, a University of Texas Southwestern Medical Center team describes a gene editing approach for correcting a hypertrophic cardiomyopathy (HCM)-linked MYH7 beta-myosin-coding gene mutation in human cardiomyocyte cells generated from induced pluripotent stem cells (iPSCs) and in a mouse model of HCM. Using their adenine base editor (ABE) approach, along with a single-guide RNA (sgRNA) approach designed to minimize off-target or bystander edits, the researchers targeted a pathogenic, missense mutation in MYH7 introduced in healthy donor iPCs with CRISPR-Cas9 editing. After testing the ABE method with several engineered deaminase enzymes, the authors applied the "ABEmax" enzyme in combination with a SpCas9-VRQR sgRNA to correct the MYH7 mutation in cardiomyocytes derived from HCM patient iPSCs — an approach they subsequently took forward to a humanized HCM mouse model. "Our findings demonstrate the potential of base editing to treat inherited cardiac diseases and prompt the further development of adenine base editor-based therapies to correct monogenic variants causing cardiac disease," they write.