Abstract 1576 Efficient in vivo Genome Editing Prevents Hypertrophic Cardiomyopathy in Mice

Dominant pathogenic variants encoding amino acid substitutions in cardiac myosin heavy chain cause hypertrophic cardiomyopathy (HCM), a currently incurable disorder that increases risk for stroke, heart failure, and sudden cardiac death. We assessed the efficacy of two different genetic therapies, an adenine base editor (ABE8e) and a potent Cas9 nuclease delivered by AAV9, to prevent disease in mice carrying the heterozygous HCM pathogenic variant myosin R403Q. One dose of dual AAV9 vectors, each carrying one half of RNA-guided ABE8e, corrected the pathogenic variant in 70% of ventricular cardiomyocytes and maintained durable, normal cardiac structure and function. An additional dose provided more global editing especially in the atria but also increased bystander editing. AAV9 delivery of RNA-guided Cas9 nuclease effectively inactivated the pathogenic allele, albeit with dose-dependent toxicities, necessitating a narrow therapeutic window to maintain health. These preclinical studies demonstrate considerable potential for single-dose genetic therapies to correct or silence pathogenic variants and prevent the development of HCM.

Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w
Efficient in vivo Genome Editing Prevents Hypertrophic Cardiomyopathy in Mice
D. Reichart¹, G. Newby², H. Wakimoto³, M. Lun³, J. Gorham³, J. Curran³, A. Raguram², D. DeLaughter³, D. Conner³, J. Marsiglia³, S. Kohli², L. Chmatal⁴, D. Page⁴, N. Zabaleta⁵, L. Vandenberghe⁵, D. Liu², J. Seidman³, C. Seidman³
¹Medizinische Klinik und Poliklinik I, LMU Klinikum der Universität München, München; ²Broad Institute of Harvard and MIT, Cambridge, US; ³Genetics Department, Harvard Medical School, Boston, US; ⁴Whitehead Institute, Cambridge, US; ⁵Mass Eye and Ear, Grousbeck Gene Therapy Center, Boston, US;
Dominant pathogenic variants encoding amino acid substitutions in cardiac myosin heavy chain cause hypertrophic cardiomyopathy (HCM), a currently incurable disorder that increases risk for stroke, heart failure, and sudden cardiac death. We assessed the efficacy of two different genetic therapies, an adenine base editor (ABE8e) and a potent Cas9 nuclease delivered by AAV9, to prevent disease in mice carrying the heterozygous HCM pathogenic variant myosin R403Q. One dose of dual AAV9 vectors, each carrying one half of RNA-guided ABE8e, corrected the pathogenic variant in 70% of ventricular cardiomyocytes and maintained durable, normal cardiac structure and function. An additional dose provided more global editing especially in the atria but also increased bystander editing. AAV9 delivery of RNA-guided Cas9 nuclease effectively inactivated the pathogenic allele, albeit with dose-dependent toxicities, necessitating a narrow therapeutic window to maintain health. These preclinical studies demonstrate considerable potential for single-dose genetic therapies to correct or silence pathogenic variants and prevent the development of HCM.
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