Single-AAV-mediated cardiomyocyte-specific adenine base editing ameliorates cardiac hypertrophy in vivo

A single-AAV, cardiomyocyte-specific adenine base editor corrected the MYBPC3 Dutch founder mutation (c.2827C>T, p.Arg943Ter) and ameliorated cardiac hypertrophy in an HCM mouse model.

• Why it matters: HCM is commonly driven by sarcomeric gene variants, yet existing therapies mainly manage symptoms; AAV base editing is promising but dual-AAV SpCas9 editors raise dose, toxicity, and cost issues.
• What they did: The team compared compact base editors in hiPSC-derived cardiomyocytes, then used a single next-generation cardiotropic AAV capsid with a 6C2 promoter to fit the editor/guide construct. They screened promoters for expression in hiPSC-CMs and cardiac tissue of mice and NHP and delivered the editor in an HCM mouse model.
• The result: Single-AAV treatment achieved therapeutic correction at doses 20-fold below published dual-AAV cardiomyopathy base editing approaches, reversing disease-associated hypercontractility in engineered human myocardium.

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