DMD gene therapy can repair muscle fibers but fails to halt tissue scarring
Fibrosis may hit ‘point of no return’ and become self-sustaining: 3D human model
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A new 3D model of Duchenne muscular dystrophy (DMD) reveals that while gene therapy can bolster muscle strength, it may be unable to halt the progressive scarring that drives the disease, according to a study by researchers at Genethon.
Findings suggest that “microdystrophin” gene therapies, similar to several currently in clinical use, successfully improve muscle contractions but leave harmful fibrotic pathways active.
Using an advanced 3D model developed from patient stem cells, scientists were able to simulate the complex environment of human muscle more accurately than before. This approach provides a critical explanation for why some patients in clinical trials see only modest improvements: the therapy fixes the muscle protein, but the body’s “scarring program” continues to run in the background.
The data highlight a major hurdle in treating advanced DMD. According to the research team, there may be a “point of no return” where tissue scarring becomes self-sustaining, suggesting that future treatments may need to combine gene therapy with anti-fibrotic drugs to be fully effective.
The study, “Disease exacerbation in human DMD MYOrganoids enables gene therapy evaluation and unveils persistence of fibrotic activity,” was published in the journal npj regenerative medicine.
Understanding the role of dystrophin and fibrosis
DMD is a rare, inherited condition that mainly affects boys and leads to progressive muscle weakness. The disease is caused by mutations in the DMD gene that disrupt the production of dystrophin, a key protein for muscle health.
Without dystrophin, muscle cells are easily damaged during normal movement. This constant injury triggers chronic inflammation and the buildup of tough, fibrous scar tissue (fibrosis). As this scarring replaces healthy muscle, it reduces the muscle’s ability to contract and significantly accelerates the loss of mobility.
“Besides being a critical driver of DMD progression, fibrosis also hampers gene therapy efficacy and is therefore paramount to counteract this process that is well-established in patients,” the investigators wrote.
Gene therapies for DMD often rely on adeno-associated viruses to deliver a functional dystrophin protein. While this approach has shown remarkable success in animal models, human results have been more modest, partly because animal models don’t always capture the full extent of human muscle scarring.
“It appears, therefore, crucial to develop time and cost-effective high-throughput models, mimicking the severity of human DMD pathology [disease] and its intricate molecular network, suitable for research investigation and therapeutic screening,” the team added.
To bridge this gap, Genethon researchers developed “MYOrganoids,” or 3D human muscle models grown from reprogrammed stem cells. By incorporating fibroblasts (the cells responsible for scarring), the team created a more realistic environment that mimics the fatigue and muscle force loss seen in real-world DMD patients. Of note, Genethon is developing a DMD gene therapy called GNT0004.
At the molecular level, the therapy successfully repaired muscle structure and reduced inflammation. However, it failed to flip the switch on fibrosis. Key drivers of scarring, such as the TGF-beta signaling pathway, remained “abnormally active.”
Identifying a point of no return for fibrosis
These findings suggest that in advanced DMD, muscle scarring may reach a “point of no return.” This insight highlights fibrosis as a major hurdle for the medical community.
Results showed a dose-dependent improvement in muscle performance. At higher doses, microdystrophin significantly reduced muscle force loss during repeated contractions and improved the rate of muscle relaxation after exertion, which are signs of rescued muscle function, according to the investigators.
The gene therapy also restored dystrophin levels in a large proportion of muscle fibers and partially normalized components of the dystrophin-associated protein complex, which helps stabilize muscle cell membranes.
Overall, the MYOrganoid platform provides “a valuable tool to bridge the translational gap either for the investigation of mechanisms driving dystrophic process and as a human in vitro counterpart to animal in vivo preclinical studies, with the potential to accelerate the identification of new treatments,” the researchers concluded.
