Researchers at Duke University School of Medicine have reimagined cancer immunotherapy as a potential treatment for Duchenne muscular dystrophy, a severe, inherited muscle disorder that has no cure. In pre-clinical models, the experimental approach improved muscle regeneration and function.
The therapy adapts CAR-T cell technology to eliminate inflammation-driving cells that build up around damaged muscle. Researchers identified a protein called uPAR on the surface of these cells and then modified the body’s own T cells to recognize the marker and eliminate its carriers.
“We used CAR-T therapy to reprogram the muscle environment,” said Yarui Diao, PhD, senior author of the study, published October 29 in Cell Stem Cell.
Duchenne muscular dystrophy primarily affects boys. Most lose the ability to walk during their teens and later develop respiratory and cardiac muscle weakness, which can lead to death in early adulthood. While supportive care such as steroids and newer gene therapies can slow progression, there is still no cure.
Rather than fixing the genetic defect or the damaged muscle fibers directly, the Duke-led approach aims to improve the muscle’s natural ability to repair itself.
“We used CAR-T therapy to reprogram the muscle environment." — Yarui Diao, PhD
Treated mice showed reduced inflammation and fibrosis, preserved muscle stem and progenitor cells, and improved muscle strength. “The treatment also improved diaphragm pathology and respiratory function — an especially important finding because respiratory failure remains a major cause of death in this disease,” Diao said.
The work was led by postdoctoral associate Hamayl Afzal, PhD, in the Diao lab and involved collaboration with Duke biomedical engineer Charlie Gersbach, PhD, to establish the CAR-T system, and pediatrician Mai ElMallah, MBBS, who helped evaluate muscle physiology and pathology.
Duke and Nationwide Children’s Hospital provided patient samples, which were used to validate that the pathological cells that express uPAR found in mouse models were also present in damaged human muscle.
Diao said the study opens the door to many exciting new research directions, including testing whether uPAR CAR-T therapy can be combined with FDA-approved gene therapies for the disease. “One important question is whether remodeling the muscle microenvironment could allow a lower dose of gene therapy to achieve a similar or greater therapeutic benefit, while reducing dose-related toxicity, which is a key bottleneck for current Duchenne muscular dystrophy gene therapy,” he said.
Other Duke authors: Tomer Rotstein, Debolina D. Biswas, Xin Lin, Alistair Khodabukus, Wenzhe Luo, Yueyuan Xu, Emma C. Frair, Yongwu Li, Jingjuan Chen, Shihuan Kuang, Nenad Bursac.
Funding: The Glenn Foundation for Medical Research, the American Federation for Aging Research, the National Institutes of Health, the Duke-Coulter Translational Partnership, the Gilbert Family Foundation, the Oxford-Harrington Rare Disease Scholar Award, the Center for Advanced Genomic Technologies at Duke.