The muscular dystrophies are genetic muscle-wasting disorders, and Duchenne muscular dystrophy (DMD) in particular has seen a rush of new therapies — gene transfer, exon skipping, and the first non-steroidal small molecules. But the past two years have also delivered a hard lesson about the risks of AAV gene therapy, which any current account must reflect honestly.
Duchenne: gene therapy — promise, and a serious safety reckoning
Delandistrogene moxeparvovec (Elevidys) was the first approved DMD gene therapy, an AAVrh74 vector delivering a shortened "micro-dystrophin," granted accelerated approval in 2023 and later expanded to non-ambulatory patients. That trajectory has since reversed sharply. In 2025, cases of fatal acute liver failure occurred in non-ambulatory patients; the FDA placed the product on clinical hold, the manufacturer paused distribution, and in November 2025 the label gained a boxed warning for acute serious liver injury and acute liver failure, with the indication restricted back to ambulatory patients aged four and older. It is now contraindicated in patients with certain exon 8/9 deletions and cautioned against in preexisting liver impairment, and the European regulator declined to recommend marketing. This sequence is a cautionary tale about AAV hepatotoxicity and immune risk — the efficacy signal (micro-dystrophin expression, functional trends) was real, but so were the harms.
Other micro-dystrophin programs (such as the investigational RGX-202) continue in trials with encouraging early expression and functional data, but the whole class now carries heightened scrutiny of liver and immune safety.
Duchenne: exon skipping, steroids, and a first non-steroidal drug
Exon-skipping antisense oligonucleotides (eteplirsen, golodirsen, viltolarsen, casimersen) restore small amounts of dystrophin in mutation-specific subgroups, with modest functional benefit and generally mild injection-related and GI effects. Corticosteroids (prednisone, deflazacort) remain standard of care for slowing progression, and vamorolone (Agamree), a newer dissociative steroid, offers comparable benefit with a more favorable bone-and-growth safety profile. The notable addition is givinostat (Duvyzat), an oral HDAC inhibitor approved in 2024 — the first non-steroidal drug for DMD that works across all genetic variants (ambulatory patients aged six and older). Its Phase 3 EPIDYS trial showed a smaller decline in stair-climbing ability; adverse effects include thrombocytopenia, GI symptoms, and raised triglycerides.
Limb-girdle and myotonic dystrophy
For limb-girdle muscular dystrophy (notably LGMD2E/beta-sarcoglycanopathy), AAV gene-transfer approaches remain in early-phase trials, showing improved muscle function and reduced creatine kinase with mostly mild infusion reactions and transient liver enzyme rises. For myotonic dystrophy type 1, RNA-targeting strategies (antisense oligonucleotides and small molecules aimed at the toxic expanded CUG repeat) are advancing through early trials, but there is still no approved disease-modifying therapy.
| Therapy | Disease | Mechanism | Status / note |
|---|---|---|---|
| Delandistrogene moxeparvovec (Elevidys) | DMD | AAV micro-dystrophin | Approved (ambulatory only); boxed warning for fatal liver failure |
| Exon-skipping ASOs | DMD | Restore dystrophin | Mutation-specific; modest benefit |
| Givinostat (Duvyzat) | DMD | HDAC inhibitor (oral) | First non-steroidal, all variants (2024) |
| Vamorolone (Agamree) | DMD | Dissociative steroid | Steroid alternative, better safety profile |
| Corticosteroids | DMD | Anti-inflammatory | Standard of care |
| AAV gene transfer | LGMD2E | Gene replacement | Early-phase |
| RNA-targeting agents | DM1 | Neutralize toxic RNA | Investigational |
Further reading: Elevidys prescribing information and FDA boxed-warning action (2025); EPIDYS givinostat trial (Lancet 2024); vamorolone approval (2023); DMD exon-skipping and gene-therapy reviews (2025).