Two independent research teams have achieved significant breakthroughs in developing CRISPR-based gene therapies for multisystemic smooth muscle dysfunction syndrome (MSMDS), a rare and often fatal pediatric disease that affects fewer than 1,000 people in the United States. The parallel advances, published in Nature Biomedical Engineering and Circulation, demonstrate the potential for customized gene editing to treat genetic vascular diseases that have previously had no effective treatments.
MSMDS is caused by mutations in the ACTA2 gene, which encodes smooth muscle actin protein. The disease leads to widespread dysfunction in smooth muscles found in blood vessels and hollow organs, causing stroke, aortic dissection, and death in childhood. Patients develop problems affecting the lungs, gastrointestinal system, kidneys, bladder, and eyes, with significantly increased vulnerability to life-threatening aortic aneurysms and dissections.
Engineered Base Editors Target Vascular Tissue
Researchers at Mass General Brigham, led by Benjamin Kleinstiver, PhD, and Patricia Musolino, MD, PhD, developed a bespoke CRISPR-Cas9 gene-editing enzyme specifically designed to correct ACTA2 mutations. Their approach uses base editing technology, which comprises a CRISPR-Cas9 protein fused to a DNA-modifying enzyme that can make precise single-letter changes to the genetic code.
"The story of this research truly began at the bedside," said Dr. Musolino of the Department of Neurology at Massachusetts General Hospital. "An infant in critical condition first brought together our team, which includes experts on the clinical, genetic, biological and therapeutic aspects of this disease. Now, we have a clear roadmap toward bringing an experimental drug back to the bedside."
The team discovered that conventional base editors effectively corrected the ACTA2 mutation but also caused unwanted changes to nearby DNA, negating the therapeutic benefits. In response, they designed and screened dozens of base editors with custom-made Cas9 proteins to improve targeting precision while minimizing off-target effects.
Dramatic Survival Benefits in Preclinical Models
The Mass General Brigham therapy demonstrated remarkable efficacy in mouse models of MSMDS. A single dose of the bespoke gene-editing treatment extended survival four-fold compared to untreated animals. Mice treated with a viral vector encoding the base editor showed improvement in both brain and aortic disease, with enhanced exercise tolerance and reduced neurodegeneration.
To deliver the therapy specifically to affected vascular tissue, Casey Maguire, PhD, designed a viral vector that targets smooth muscle cells lining blood vessels. This represents the first CRISPR-based therapeutic approach designed specifically to target the vasculature in rapidly progressing pediatric vascular disease.
Parallel Success at UT Southwestern
Simultaneously, researchers at UT Southwestern Medical Center, led by Eric Olson, PhD, Ning Liu, PhD, and Qianqian Ding, PhD, achieved similar success using base editing to prevent MSMDS symptoms before they developed. Their findings, published in Circulation, demonstrated functional correction in smooth muscle cells, which are notoriously difficult to target.
"Gene editing has been used in other disease contexts, but its application to inherited vascular diseases, particularly targeting smooth muscle cells in vivo, is still emerging," said Dr. Olson, Chair and Professor of Molecular Biology. "Our approach advances the field by demonstrating functional correction in a cell type that's notoriously difficult to target."
The UT Southwestern team first validated their approach in human smooth muscle cells carrying mutant ACTA2 in laboratory dishes. After introducing base editing components, they successfully corrected the disease-causing mutation and resolved pathological traits including inability to contract and excessive cell proliferation and migration.
Early Intervention Shows Promise
The UT Southwestern researchers then tested their therapy in mice carrying the human ACTA2 mutation. Animals that received the base editing components three days after birth remained healthy, while untreated mice developed characteristic MSMDS symptoms including enlarged bladders and kidneys, dilated small intestines, and weakened aortas.
"This strategy might be effective in human patients early in their disease process – an approach the team hopes will eventually be tested in clinical trials," Dr. Ding explained. The researchers plan to investigate whether gene editing could reverse symptoms after they've developed and explore applications for other genetic smooth muscle diseases.
Regulatory Progress and Clinical Translation
Both research teams have made significant progress toward clinical translation. The Mass General Brigham team has already engaged with the U.S. Food and Drug Administration, paving the way for clinical trials. With guidance from Mass General Brigham's Innovation team and the Gene and Cell Therapy Institute, the program has advanced toward IND filing and secured FDA rare disease designations – milestones that will accelerate development.
"Our lab has made progress in engineering base editors to be safer, more effective, more precise, and therefore better suited to treating genetic disease," said Dr. Kleinstiver, an investigator in the Center for Genomic Medicine at MGH. His team recently designed a CRISPR-Cas9 enzyme that helped save the life of an infant born with a rare metabolic disease.
Broader Therapeutic Implications
The research may have applications beyond MSMDS for other vascular conditions. According to the Mass General Brigham team, this work could advance cures for moyamoya, Marfan syndrome, Loeys-Dietz syndrome, and even atherosclerosis – a leading cause of cardiovascular disease and the most common cause of death worldwide according to the World Health Organization.
"The impact of this work extends beyond just one disease," said Mark Lindsay, MD, PhD, a pediatric cardiologist within the Mass General Brigham Heart and Vascular Institute. "Our team has created tools that have accelerated the field of genome-editing and precision therapeutics to levels that were unthinkable just two years ago. Cures are possible, but only if we continue to support biomedical research."
