Addressing Duchenne Muscular Dystrophy Challenges: Potential Benefits of Gene Transfer Therapy
Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by the absence or near absence of functional dystrophin protein, leading to severe muscle weakness and early mortality, often before age 30. Current treatments, such as supportive ventilation and corticosteroids, can delay disease progression but are associated with side effects. Not all DMD patients benefit from existing therapies, according to a study published in Muscle & Nerve.
Delandistrogene moxeparvovec is a gene transfer therapy designed to address the root cause of DMD. It uses a viral vector to deliver microdystrophin protein to skeletal and heart muscles, aiming to restore functional domains. A phase 1/2a clinical trial evaluated the safety and functional outcomes of delandistrogene moxeparvovec in patients aged ≥4 to <8 years. The treatment was well-tolerated, with no serious adverse events reported. It showed a significant increase in the expression of microdystrophin protein, improvement in functional assessments, and the restoration of dystrophin-associated protein complex. These positive outcomes were sustained for up to 4 years.
Safety data revealed 72 adverse events, 25% being treatment-related, primarily mild or moderate in severity, and all resolving within the first 70 days post-treatment. Notably, no new treatment-related adverse events occurred after this period. The most common side effects included vomiting and upper respiratory tract infections. No significant abnormalities were observed in laboratory parameters, including serum creatine kinase levels and echocardiograms.
Functional assessments, including the North Star Ambulatory Assessment (NSAA) and timed function tests, demonstrated sustained improvements in motor function over the 4-year follow-up period. Patients treated with delandistrogene moxeparvovec showed a significant and clinically meaningful difference in change from baseline NSAA scores compared to a control group.
While the study acknowledges limitations such as its small sample size and the need for continuous long-term monitoring, it suggests that delandistrogene moxeparvovec is well-tolerated and leads to a sustained stabilization of motor function in DMD patients, potentially offering a promising therapeutic option.
"Functional assessments demonstrated long-term sustained stabilization of motor function that was clinically meaningful and, importantly, at ages when functional decline is expected based on natural history. In addition, as evidenced by functional results, our study suggests durable expression of delandistrogene moxeparvovec dystrophin protein from an episomal genome in muscle cells," said researchers.
Reference
Mendell JR, Zarife Sahenk, Lehman K, et al. Long‐term safety and functional outcomes of delandistrogene moxeparvovec gene therapy in patients with Duchenne muscular dystrophy: A phase 1/2a nonrandomized trial. Muscle & Nerve. Published online August 14, 2023. Accessed October 2, 2023. doi:10.1002/mus.27955
