Efficient precise in vivo base editing in adult dystrophic mice.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34140489.
- Also identified by DOI 10.1038/s41467-021-23996-y and PMC identifier 8211797.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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 mdx<sup>4cv</sup> 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.
Medical subject headings
- CRISPR-Cas Systems
- Dystrophin
- Gene Editing
- Genetic Therapy
- Muscle Fibers, Skeletal
- Muscle, Skeletal
- Muscular Dystrophy, Duchenne