Duchenne muscular dystrophy (DMD) is the most severe and common hereditary myopathy in childhood, affecting 1 in 3,500-5,000 males. Caused by mutations in the dystrophin gene on the X chromosome, it produces progressive muscle weakness leading to loss of ambulation before age 12, respiratory failure, and dilated cardiomyopathy. In 2026, three gene therapy strategies have entered phase III trials and the first has received regulatory approval.
Dystrophin and molecular pathogenesis
Dystrophin is a 427 kDa structural protein connecting the myocyte actin cytoskeleton to the extracellular matrix through the dystrophin-associated protein complex (DAPC). Without dystrophin, the sarcolemmal membrane is fragile and the contraction-relaxation cycle produces repeated mechanical damage, inflammation, necrosis, and replacement by fibroadipose tissue.
Exon skipping: from concept to drug
Exon 51 skipping restores the DMD mRNA reading frame in 13% of patients with the appropriate mutation, generating a truncated but partially functional dystrophin. Eteplirsen (Exondys 51) was the first antisense oligonucleotide FDA-approved in 2016. In 2026, casimersen (exon 45) and viltolarsen (exon 53) are approved, extending treatment to 8-10% additional patients. Real-world data at 3-5 years shows modest but consistent slowing of functional loss in ambulatory patients.
Gene therapy with micro-dystrophin: SRP-9001 results
Delandistrogene moxeparvovec (SRP-9001, Elevidys) received accelerated FDA approval in June 2023 for patients aged 4-5 years with genetically confirmed DMD. The EMBARK phase 3 trial (n=125) at 52 weeks showed significant increase in micro-dystrophin expression (p<0.0001) and modest functional improvement on the NSAA scale. Treatment cost — estimated at $3.2 million per patient for a single infusion — has generated intense debate about access and sustainability.
CRISPR-based therapy: permanent DNA correction
First-in-human CRISPR trials for DMD are in phase I/II in 2026. Genomic exon skipping via CRISPR-Cas9 delivered by AAV is permanent, unlike mRNA skipping with oligonucleotides. The main barrier is immunogenicity against Cas9 proteins and neutralizing antibodies against AAV vectors, which limit the possibility of re-administration.
Current standard treatment
While gene therapies mature, standard treatment includes deflazacort or prednisone (reducing functional loss by 30-40%), atalureno for nonsense mutations, physiotherapy, and nocturnal non-invasive ventilation. Vamorolone, a dissociative steroid with fewer metabolic side effects, received FDA approval in 2023 as an alternative to classical corticosteroids.
