Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice

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…

• NS
  National Science Foundation
• HH
  Howard Hughes Medical Institute
• HH
  Helen Hay Whitney Foundation
• BH
  British Heart Foundation

  Award: BBC/F/21/220106
• DF
  Deutsche Forschungsgemeinschaft
• NI
  National Institutes of Health

  Awards: GM118062, R35 GM118062, HL080494, HL084553, U01 AI142756, HG009490, RM1 HG009490
• OO
  Office of Extramural Research, National Institutes of Health

  Awards: HL080494, RM1 HG009490, U01 AI142756, HL084553, R35 GM118062