Efficient precise in vivo base editing in adult dystrophic mice

Nat Commun. 2021 Jun 17;12(1):3719. doi: 10.1038/s41467-021-23996-y.


Recent advances in base editing have created an exciting opportunity to precisely correct disease-causing mutations. However, the large size of base editors and their inherited off-target activities pose challenges for in vivo base editing. Moreover, the requirement of a protospacer adjacent motif (PAM) nearby the mutation site further limits the targeting feasibility. Here we modify the NG-targeting adenine base editor (iABE-NGA) to overcome these challenges and demonstrate the high efficiency to precisely edit a Duchenne muscular dystrophy (DMD) mutation in adult mice. Systemic delivery of AAV9-iABE-NGA results in dystrophin restoration and functional improvement. At 10 months after AAV9-iABE-NGA treatment, a near complete rescue of dystrophin is measured in mdx4cv mouse hearts with up to 15% rescue in skeletal muscle fibers. The off-target activities remains low and no obvious toxicity is detected. This study highlights the promise of permanent base editing using iABE-NGA for the treatment of monogenic diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems*
  • Cell Line
  • Dependovirus
  • Disease Models, Animal
  • Dystrophin / genetics*
  • Dystrophin / metabolism
  • Gene Editing / methods*
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Humans
  • Mice
  • Mice, Inbred mdx
  • Muscle Fibers, Skeletal / metabolism*
  • Muscle Fibers, Skeletal / pathology
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscular Dystrophy, Duchenne / genetics*
  • Muscular Dystrophy, Duchenne / metabolism
  • Muscular Dystrophy, Duchenne / pathology
  • Muscular Dystrophy, Duchenne / therapy
  • Mutation
  • RNA-Seq


  • Dystrophin