We developed a customized base editing strategy to efficiently, precisely and safely correct the most common ACTA2 pathogenic mutation in multisystemic smooth muscle dysfunction syndrome. In vivo delivery of the bespoke base editor prolongs survival and rescues systemic phenotypes in a mouse model of multisystemic smooth muscle dysfunction syndrome.
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References
Milewicz, D. M. et al. De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction. Am. J. Med. Genet. A 152A, 2437–2443 (2010). This paper reports the characterization of MSMDS as resulting from mutations in ACTA2.
Gaudelli, N. M. et al. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature 551, 464–471 (2017). This paper reports the development of ABEs, which catalyse adenine to guanine base edits.
Kleinstiver, B. P. et al. Engineered CRISPR-Cas9 nucleases with altered PAM specificities. Nature 523, 481–485 (2015). This paper reports the engineering of an SpCas9 variant enzyme that can target a non-canonical PAM, which expands ABE accessibility to genomic target sites with NGA PAMs.
Silverstein, R. A. et al. Custom CRISPR–Cas9 PAM variants via scalable engineering and machine learning. Nature 643, 539–550 (2025). This paper combines protein engineering and machine learning to develop a large catalogue of thousands of bespoke PAM-specific enzymes for use with base editors.
Musunuru, K. et al. Patient-specific in vivo gene editing to treat a rare genetic disease. N. Engl. J. Med. 392, 2235–2243 (2025). This report describes the rapid development of a bespoke treatment, comprising a customized ABE, for an infant with a severe metabolic disease.
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This is a summary of: Alves, C. R. R. et al. Treatment of a severe vascular disease using a bespoke CRISPR–Cas9 base editor in mice. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-025-01499-1 (2025).
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Engineering of a bespoke CRISPR base editor to treat a severe vascular disease. Nat. Biomed. Eng (2025). https://doi.org/10.1038/s41551-025-01510-9
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DOI: https://doi.org/10.1038/s41551-025-01510-9
