Gene editing treats smooth muscle disease in preclinical model
UTSW findings could lead to therapies for rare syndrome linked to inherited vascular conditions, other health problems
DALLAS – June 23, 2025 – Using gene editing in a preclinical model, researchers at UT Southwestern Medical Center blocked the symptoms of a rare smooth muscle disease before they developed. Their findings, published in Circulation, could eventually lead to gene therapies for this and other genetic diseases affecting smooth muscle cells.
“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. Our approach advances the field by demonstrating functional correction in a cell type that’s notoriously difficult to target,” said Eric Olson, Ph.D., Chair and Professor of Molecular Biology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. Dr. Olson co-led the study with Ning Liu, Ph.D., Professor of Molecular Biology, and first author Qianqian Ding, Ph.D., postdoctoral researcher, both members of the Olson Lab.
Fewer than 1,000 people in the U.S. have multisystem smooth muscle dysfunction syndrome (MSMDS). This disease is marked by widespread disorders in smooth muscles, a type of non-striated contractile tissue found in blood vessels and various hollow organs.
Patients with MSMDS develop problems affecting the lungs, gastrointestinal system, kidneys, bladder, and eyes beginning in childhood. They are also significantly more vulnerable to aortic aneurysms and aortic dissections – medical emergencies affecting the body’s largest artery that necessitate emergency surgery to prevent sudden death.
Because MSMDS is often caused by a single nucleotide mutation – a pathological change in one “letter” of the genetic code, in this case in a gene called ACTA2 – gene therapy could theoretically cure patients with this disease, Dr. Ding explained. However, no gene therapies developed thus far have successfully targeted smooth muscle tissues.
To look for a possible solution, Drs. Ding, Liu, and Olson and their colleagues used a strategy called base editing – a variation of the CRISPR gene editing method that uses targeted molecular machinery to swap one specific letter of the genetic code for another, converting a mutant gene to its healthy form. The researchers tested this approach first in human smooth muscle cells carrying mutant ACTA2. After introducing the base editing components into mutant cells growing in petri dishes, the scientists showed that the disease-causing mutant version of ACTA2 was corrected. This treatment resolved pathological traits seen in the mutant cells, including an inability to contract and excessive proliferation and migration.
While this gene editing strategy appeared to be successful in cells, Dr. Ding explained, applying it in whole organisms was far more challenging because the base editing machinery must be expressed specifically in smooth muscle cells. To achieve this, they packaged them with a promoter – a DNA fragment that ensures genes are expressed in the right cell type. Mice carrying the human ACTA2 mutation responsible for MSMDS that received the base editing components three days after birth remained healthy, while untreated mice developed 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. They plan to investigate in future studies whether gene editing could reverse symptoms of MSMDS after they’ve developed and whether their approach could hold promise for other genetic smooth muscle diseases.
Other UTSW researchers who contributed to this study are Lin Xu, Ph.D., Assistant Professor in the Peter O’Donnell Jr. School of Public Health and of Pediatrics; Hui Li, Ph.D., and John McAnally, B.S., Senior Research Scientists; Lei Guo, Ph.D., Computational Biologist; Camryn MacDonald, B.S.A., Research Assistant; Wei Tan, M.D., and Efrain Sanchez-Ortiz, Ph.D., Research Scientists; and Peiheng Gan, Ph.D., M.B.B.S., and Zhisheng Xu, Ph.D., postdoctoral researchers.
Dr. Olson, Director of the Hamon Center for Regenerative Science and Medicine, holds The Robert A. Welch Distinguished Chair in Science, the Pogue Distinguished Chair in Research on Cardiac Birth Defects, and the Annie and Willie Nelson Professorship in Stem Cell Research.
This study was funded by grants from the National Institutes of Health (R01HL130253, R01HL157281, P50HD087351), The Welch Foundation (1-0025), The Leducq Foundation Transatlantic Networks of Excellence, the British Heart Foundation’s Big Beat Challenge award to CureHeart (BBC/F/21/220106), and the American Heart Association (25POST1372779).
About UT Southwestern Medical Center 
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.