Custom Gene Editor Shows Promise for Rare Vascular Disease Treatment

A groundbreaking gene editing technique developed by researchers at Mass General Brigham in Boston has successfully corrected a mutation responsible for a rare and deadly blood vessel disease in mice, opening new avenues for treating genetic vascular disorders.

Innovative Approach to Multisystemic Smooth Muscle Dysfunction Syndrome

Multisystemic smooth muscle dysfunction syndrome (MSMDS), an extremely rare genetic condition, has been the focus of a collaborative effort led by Benjamin Kleinstiver, Ph.D., a genome engineer at Mass General Hospital and Harvard Medical School. The disease, caused by a single nucleotide mutation in the ACTA2 gene, disrupts the function of smooth muscle cells throughout the body, leading to severe complications and early mortality.

The research team designed a custom gene editing technique that specifically targets the ACTA2 mutation. In a mouse model of MSMDS, all treated animals survived to the eight-week mark, while untreated mice did not survive. These promising results, published in Nature Biomedical Engineering on September 11, 2025, have paved the way for potential human trials.

Advancing Personalized Gene Therapy

The approach used in this study bears similarities to the personalized CRISPR therapy recently employed to treat an infant with a rare metabolic disease. However, Kleinstiver's team has adapted the technique to target smooth muscle cells using a viral vector, rather than focusing on the liver with lipid nanoparticles.

The breakthrough came with the application of new base editors, released by David Liu's lab in 2020. These editors, when paired with a Cas9 enzyme, can swap individual DNA letters without breaking the DNA strands. The team further refined these tools to achieve high specificity for the ACTA2 gene location.

Collaborative Efforts and Future Prospects

The research project emerged from a collaboration between Kleinstiver's lab and that of Patricia Musolino, M.D., Ph.D., a vascular neurologist with extensive experience treating MSMDS patients. "The story of this research truly began at the bedside," Musolino stated, emphasizing the translational nature of their work.

With promising results in hand, the team has already engaged with the FDA through INTERACT and pre-IND meetings to discuss their plans for human trials. This development represents one of the first examples of customized gene editing for vascular disease and could potentially lead to treatments for other genetic vascular disorders.

As the pharmaceutical industry continues to explore the potential of gene editing technologies, this breakthrough offers hope for patients with rare genetic conditions and underscores the importance of collaborative, multidisciplinary research in advancing medical treatments.