A single liver-sparing myotropic AAV ameliorates muscular dystrophy in humanized mice by base editing.
6 affiliations
- 1Department of Molecular Biology
- 2Hamon Center for Regenerative Science and Medicine, and
- 3Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
- 4Grousbeck Gene Therapy Center, Schepens Eye Research Institute, and Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.
- 5The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
- 6Cima Universidad de Navarra, Pamplona, Spain.
Abstract
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, most of which are large exon deletions that result in loss of dystrophin protein. Adenine base editing (ABE) enables permanent gene correction by modifying splice sites to cause exon skipping and restoration of the DMD open reading frame. We previously demonstrated that adeno-associated virus 9-mediated (AAV9-mediated) delivery of adenine base editors allows efficient gene editing in mouse models of DMD. However, conventional AAV-based gene delivery approaches are complicated by their limited packaging capacity and high-dose-related toxicity. Here, we describe a single AAV vector encoding a compact adenine base editor, SlugABE8e, and a single-guide RNA, which enable efficient editing in a humanized DMD mouse model at a lower dose using the muscle-tropic MyoAAV4 capsid. Systemic MyoAAV4A delivery in juvenile DMD mice efficiently restored dystrophin expression in the heart and skeletal muscles. This molecular rescue was accompanied by reduced serum creatine kinase activity and diminished muscle pathology. A liver-detargeted MyoAAV4E-off capsid eliminated viral entry and editing in the liver. We also explored a high-fidelity base editor, SlugHF-ABE8e(V106W), which showed similar on-target and off-target editing to SlugABE8e. Together, these findings establish an all-in-one AAV strategy that efficiently mitigates DMD disease progression.
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BibTeX
@article{pien2026single,
title = {{A single liver-sparing myotropic AAV ameliorates muscular dystrophy in humanized mice by base editing.}},
author = {Yu-Chung Pien and Hui Li and Gabrielle Bulliard and Huachun Liu and Mateusz Z. Durbacz and Zhisheng Xu and Andreas C. Chai and Francesco Chemello and Efrain Sanchez-Ortiz and Nerea Zabaleta and Luk H. Vandenberghe and Ning Liu and Eric N. Olson},
journal = {The Journal of clinical investigation},
year = {2026},
month = nov,
doi = {10.1172/jci202378},
url = {https://europepmc.org/article/MED/42969232},
note = {CC BY},
}
RIS
TY - JOUR
TI - A single liver-sparing myotropic AAV ameliorates muscular dystrophy in humanized mice by base editing.
AU - Yu-Chung Pien
AU - Hui Li
AU - Gabrielle Bulliard
AU - Huachun Liu
AU - Mateusz Z. Durbacz
AU - Zhisheng Xu
AU - Andreas C. Chai
AU - Francesco Chemello
AU - Efrain Sanchez-Ortiz
AU - Nerea Zabaleta
AU - Luk H. Vandenberghe
AU - Ning Liu
AU - Eric N. Olson
PY - 2026
DA - 2026/11/02
JO - The Journal of clinical investigation
DO - 10.1172/jci202378
UR - https://europepmc.org/article/MED/42969232
AB - Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, most of which are large exon deletions that result in loss of dystrophin protein. Adenine base editing (ABE) enables permanent gene correction by modifying splice sites to cause exon skipping and restoration of the DMD open reading frame. We previously demonstrated that adeno-associated virus 9-mediated (AAV9-mediated) delivery of adenine base editors allows efficient gene editing in mouse models of DMD. However, conventional AAV-based gene delivery approaches are complicated by their limited packaging capacity and high-dose-related toxicity. Here, we describe a single AAV vector encoding a compact adenine base editor, SlugABE8e, and a single-guide RNA, which enable efficient editing in a humanized DMD mouse model at a lower dose using the muscle-tropic MyoAAV4 capsid. Systemic MyoAAV4A delivery in juvenile DMD mice efficiently restored dystrophin expression in the heart and skeletal muscles. This molecular rescue was accompanied by reduced serum creatine kinase activity and diminished muscle pathology. A liver-detargeted MyoAAV4E-off capsid eliminated viral entry and editing in the liver. We also explored a high-fidelity base editor, SlugHF-ABE8e(V106W), which showed similar on-target and off-target editing to SlugABE8e. Together, these findings establish an all-in-one AAV strategy that efficiently mitigates DMD disease progression.
SN - 0021-9738
SN - 1558-8238
ER -