Efficient precise in vivo base editing in adult dystrophic mice

Li Xu, Chen Zhang, Haiwen Li, Peipei Wang, Yandi Gao, Nahush A. Mokadam, Jianjie Ma, W. David Arnold and Renzhi Han ()
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Li Xu: The Ohio State University Wexner Medical Center
Chen Zhang: The Ohio State University Wexner Medical Center
Haiwen Li: The Ohio State University Wexner Medical Center
Peipei Wang: The Ohio State University Wexner Medical Center
Yandi Gao: The Ohio State University Wexner Medical Center
Nahush A. Mokadam: The Ohio State University Wexner Medical Center
Jianjie Ma: The Ohio State University Wexner Medical Center
W. David Arnold: The Ohio State University Wexner Medical Center
Renzhi Han: The Ohio State University Wexner Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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 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.

Date: 2021
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DOI: 10.1038/s41467-021-23996-y

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