ArticleNature biomedical engineering2026
Treatment of a severe vascular disease using a bespoke CRISPR-Cas9 base editor in mice.
Article in Nature biomedical engineering, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Precision metabolic therapy for propionic acidemia.Biochemical pharmacology · 2026Review
- On-target and off-target activities of CRISPR therapeutics across scales.Trends in biotechnology · 2026Review
- Towards precision medicine for brain arteriovenous malformations.The Journal of clinical investigation · 2026Review
- Treatment of a severe vascular disease using a bespoke CRISPR-Cas9 base editor in mice.Nature biomedical engineering · 2026Article
- Advances in Engineered Virus-Like Particles for Genome Editing and Therapy.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2026Review
- Structural and functional gastrointestinal abnormalities in ACTA2 R179H mice modeling multisystemic smooth muscle dysfunction syndrome.JCI insight · 2026Article
- Smooth Muscle Dysfunction Drives Cerebrovascular Reserve Failure and End-Organ Brain Injury.bioRxiv : the preprint server for biology · 2026Article
- Genetic Causes of Thoracic Aortic Aneurysm: A Review.Methodist DeBakey cardiovascular journal · 2026Review
- Navigating Drug Discovery for Myhre Syndrome: The Complexity of a Multisystemic Rare Disease.American journal of medical genetics. Part C, Seminars in medical genetics · 2025Review
- Review
- Current trends in gene therapy to treat inherited disorders of the brain.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Expanding the CRISPR/Cas toolkit: applications in proteomics and theranostics.Frontiers in bioengineering and biotechnology · 2025Review
Corrections and comments
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Authors and funding
33 authors.
Funding
Abstract
Pathogenic missense mutations in the alpha actin isotype 2 (ACTA2) gene cause multisystemic smooth muscle dysfunction syndrome (MSMDS), a genetic vasculopathy that is associated with stroke, aortic dissection and death in childhood. Here we perform mutation-specific protein engineering to develop a bespoke CRISPR-Cas9 enzyme with enhanced on-target activity against the most common MSMDS-causative mutation ACTA2 R179H. To directly correct the R179H mutation, we screened dozens of configurations of base editors to develop a highly precise corrective A-to-G edit with minimal deleterious bystander editing that is otherwise prevalent when using wild-type SpCas9 base editors. We create a murine model of MSMDS that shows phenotypes consistent with human patients, including vasculopathy and premature death, to explore the in vivo therapeutic potential of this strategy. Delivery of the customized base editor via an engineered smooth muscle-tropic adeno-associated virus (AAV-PR) vector substantially prolongs survival and rescues systemic phenotypes across the lifespan of MSMDS mice, including in the vasculature, aorta and brain. Our results highlight how bespoke mutant-specific CRISPR-Cas9 enzymes can improve mutation correction with base editors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.