Duchenne muscular dystrophy (DMD) is an inherited disorder that is characterized by progressive muscle degeneration, leading to loss of function and premature death. The global prevalence of DMD is approximately 19.8 per 100,000 live male births. As the genetic and molecular basis of DMD becomes better characterised, treatment strategies are increasingly mapped to specific mutation profiles and disease modifiers.
The underlying pathology of DMD impacts the function of a cytoskeletal protein, dystrophin, that is essential for muscle fiber integrity. DMD follows an X-linked recessive inheritance pattern, with thousands of distinct mutations identified in the dystrophin gene. These mutations result in varying degrees of functional disruption to dystrophin, ranging from complete absence of the protein to the production of truncated or dysfunctional forms.
Various genetic modifiers have been found to affect disease severity and treatment response. Variants in genes such as SPP1 and LTBP4 have been associated with differences in progression and steroid responsiveness, helping to explain variability even among patients with the same mutation. These modifiers not only inform prognosis but may also serve as future therapeutic targets.
Exon skipping therapy has emerged as a personalized treatment strategy for DMD. Multiple ASOs have been approved by the FDA for specific exon targets, including:
Each of these is tailored to specific deletions in DMD. These therapies aim to restore the reading frame and enable production of a truncated but partially functional dystrophin protein. While generally well tolerated with weekly intravenous administration, their clinical benefit remains modest due to low dystrophin expression levels in muscle tissue. Long-term efficacy is still under investigation, and strategies to enhance tissue delivery are under development.
Gene therapy using adeno-associated virus (AAV) vectors represents a distinct approach that aims to deliver a functional or micro-dystrophin gene directly to muscle tissue. The most advanced candidate, delandistrogene moxeparvovec-rokl (Elevidys, Sarepta Therapeutics), delivers a micro-dystrophin gene and received FDA accelerated approval in 2023 for ambulatory patients with confirmed DMD mutations. Clinical trials have shown successful gene transfer and dystrophin expression, with ongoing confirmatory studies including the ENVISION trial. However, after the death of a second patient in June 2025 due to acute liver failure, ENVISION was paused to re-evaluate the study protocol, with a specific focus on increasing immunosuppression in non-ambulatory participants receiving the therapy.
Other gene therapy products such as SGT-001 (Solid Biosciences) and PF-06939926 (Pfizer) are in clinical trials, though concerns remain around immune responses, durability of expression, and limitations on redosing. Ataluren (PTC Therapeutics), an oral read-through drug for nonsense mutations, received conditional EMA approval in 2014 but failed to meet primary endpoints in multiple randomized trials. Subgroup analyses indicated benefits in patients with intermediate levels of function, and post-marketing registries have reported extended ambulation. However, the EMA recommended non-renewal of its authorization in 2024 due to insufficient confirmatory evidence.
Progress in DMD therapy has been meaningful but uneven. Advances in exon skipping, gene therapy, and read-through mechanisms have expanded the treatment landscape, while durability, safety, and delivery constraints continue to limit clinical impact. For sponsors designing trials in this space, the heterogeneity of mutation types and the influence of genetic modifiers create meaningful stratification complexity. Eligibility criteria that fail to account for modifier profiles or expression thresholds can constrain the evaluable population, affect enrollment timelines, and complicate outcome interpretation across patient subgroups.
While there is no cure yet, the landscape of DMD therapy has changed substantially in recent years, with the FDA approving multiple mutation-specific therapies and the first gene therapy receiving accelerated approval in 2023. Ongoing confirmatory trials, improved delivery methods, and better-characterized genetic modifiers will determine how quickly and broadly effective treatments can reach patients.
For a detailed analysis of how precision medicine is shaping therapeutic development and trial design across Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and ALS, read the full report here.