Developing personalized therapies has always been a key goal of medical research. This year, the news of the first patient receiving a personalized CRISPR gene-editing therapy garnered widespread attention worldwide. This marked the first time a gene-editing therapy has been tailored to a single patient. The infant, KJ Muldoon, was diagnosed with a severe genetic disorder, carbamoyl phosphate synthetase-1 (CPS1) deficiency, just days after birth. Researchers developed a customized lipid nanoparticle (LNP)-delivered base editing therapy in just six months and validated its safety and efficacy in monkeys. The therapy successfully corrected the child's disease-causing genetic mutation and resulted in significant clinical improvement. This success has become a model for personalized therapy.
CRISPR-Cas9 and CRISPR-based base editors hold promise for treating a variety of devastating diseases, including vascular disorders. Multisystem smooth muscle dysfunction syndrome (MSMDS) is a rare vascular disease that can lead to stroke, aortic dissection, and even death in children. The most common cause of the disease is a point mutation in the ACTA2 gene.
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In September 2025, researchers from Harvard Medical School and Massachusetts General Hospital published a research paper titled "Treatment of a severe vascular disease using a bespoke CRISPR–Cas9 base editor in mice" in Nature Biomedical Engineering, a Nature journal. The study developed a customized CRISPR-Cas9 base editor that successfully treated a mouse model of multisystem smooth muscle dysfunction syndrome (MSMDS).
Figure 1. Schematic of MSMDS caused by an ACTA2 R179H mutation. (Alves C R R, et al., 2025)
There is currently no effective treatment for multisystem smooth muscle dysfunction syndrome (MSMDS). The most common mutation is ACTA2 R179H, a single-base mutation from G to A in exon 6 of the ACTA2 gene, resulting in a substitution of arginine for histidine at position 179 in the encoded protein. Using CRISPR-based base editing technology to repair the pathogenic ACTA2 mutation holds promise for developing treatments for MSMDS. However, a research team discovered that conventional SpCas9-based adenine base editors (ABEs) can produce "bystander edits," resulting in the editing of another adenine near the target site, rendering the treatment ineffective.
Therefore, the research team conducted a personalized therapy development effort. They screened for SpCas9 enzymes with enhanced targeting specificity for ACTA2 R179H, the most common pathogenic mutation in MSMDS. Building on SpCas9-VRQR, the team successfully identified an engineered SpCas9-VRQR. The base editors constructed on this basis are capable of highly precise A to G editing with minimal deleterious "bystander editing" effects.
Next, the research team created a mouse model of MSMDS that exhibits phenotypes consistent with human patients, including vascular lesions and premature death, to explore the in vivo therapeutic potential of this strategy. The team used an engineered smooth muscle-tropic adeno-associated virus (AAV-PR) vector to deliver the custom-made base editors. Results showed that this therapy significantly extended the lifespan of MSMDS mice and rescued systemic phenotypes, including those affecting the blood vessels, aorta, and brain, throughout their lifespan.
Figure 2. Phenotypic changes in MSMDS mice following AAV-mediated delivery of ABEs. (Alves C R R, et al., 2025)
This study demonstrates that customizing mutation-specific CRISPR-Cas9 enzymes can enhance the mutation correction efficacy of base editors and effectively treat severe vascular diseases in mouse models. The US FDA has granted this therapy Rare Disease Drug Designation (including Orphan Drug Designation). The research team will conduct additional toxicology studies and hopes to conduct the first human trial in 2027.
Reference
Alves C R R, et al. Treatment of a severe vascular disease using a bespoke CRISPR–Cas9 base editor in mice. Nature Biomedical Engineering, 2025: 1-16.