| First Author | Reichart D | Year | 2023 |
| Journal | Nat Med | Volume | 29 |
| Issue | 2 | Pages | 412-421 |
| PubMed ID | 36797483 | Mgi Jnum | J:362299 |
| Mgi Id | MGI:7859535 | Doi | 10.1038/s41591-022-02190-7 |
| Citation | Reichart D, et al. (2023) Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice. Nat Med 29(2):412-421 |
| abstractText | Dominant missense pathogenic variants in cardiac myosin heavy chain cause hypertrophic cardiomyopathy (HCM), a currently incurable disorder that increases risk for stroke, heart failure and sudden cardiac death. In this study, we assessed 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 editing 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. |
