Gene therapies and small molecule treatments continue to bring new hope to those living with Duchenne muscular dystrophy (DMD), even as the path forward remains complex, according to a review published recently in the European Journal of Medicinal Chemistry.
Sarepta Therapeutics recently paused global shipments of its gene therapy Elevidys, after two patients with DMD treated with Elevidys experienced fatal acute liver failure; a safety review by the U.S. Food and Drug Administration (FDA) determined the second death was unlikely to be related to Elevidys, and shipments resumed. Despite promising clinical trial outcomes, including functional gains in the ENDEAVOR study, these events raise safety questions that will likely influence future treatment protocols.
DMD is a rare, inherited disorder caused by mutations in the DMD gene, which disrupt the production of dystrophin, a protein essential for muscle integrity. Without it, muscles progressively weaken, leading to heart and breathing complications. Though standard steroid therapies help slow progression, long-term steroid use comes with major side effects, and a cure for DMD remains elusive. This has fueled global efforts to develop more precise, lasting interventions.
“Future directions include multi-target therapies (e.g., combining anti-inflammatory and anti-fibrotic agents), advanced delivery technologies (e.g., nanocarriers), personalized medicine (e.g., biomarker-guided optimization), and integration with gene therapy to improve long-term efficacy and survival,” explained this review’s authors. “While small molecule drugs hold significant potential in DMD treatment, their long-term safety and synergistic effects require further study.”
Read more about therapies for DMD
One major strategy includes gene replacement using adeno-associated virus vectors to deliver microdystrophin, which is an engineered version of dystrophin small enough to fit inside viral carriers. Elevidys is one such therapy. By helping muscle cells produce microdystrophin, it aims to restore stability to muscle fibers and prevent further damage. However, the therapy’s temporary suspension following liver toxicity cases highlights the need for better understanding of immune and organ responses to gene delivery.
Other innovative approaches include exon skipping, which uses antisense oligonucleotides to bypass faulty exons during mRNA processing, enabling production of partially functional dystrophin. Meanwhile, CRISPR-Cas9-based gene editing aims to correct genetic errors at their source, potentially offering a one-time treatment. Stem cell therapies are also in development, though challenges remain in delivering cells to damaged tissue and avoiding rejection.
In parallel to these approaches, researchers are investigating small molecule drugs to target oxidative stress and calcium overload, which are key contributors to muscle cell damage in DMD. These compounds may help stabilize cellular function and slow degeneration by reducing inflammation, restoring calcium balance and limiting mitochondrial damage.
For patients and families, these efforts mark both progress and caution. While science moves closer to more effective treatments, safety monitoring and deeper biological insights remain critical in ensuring these therapies do more good than harm.
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