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Angelini. J Transl Genet Genom 2024;8:244-8 https://dx.doi.org/10.20517/jtgg.2024.29 Page 246

[3]
several DMD trials to evaluate the effects of different corticosteroid dosing regimens . Through a detailed
comparison, the FOR-DMD trial revealed a clear efficacy profile. In this trial, 164/196 randomized DMD
boys were analyzed, showing better results with daily steroid treatment using either prednisone or DF, with
the latter resulting in less weight gain.

Vamorolone is an innovative steroid that maintains efficacy while reducing metabolic side effects . It has
[4]
been approved for DMD, and clinical trials for BMD are ongoing. Recent advances in brain imaging have
revealed abnormalities associated with dystrophinopathy, which have been linked to low IQ in one-third of
DMD cases. In both DMD and BMD, cortical atrophy is associated with ventricular dilatation and changes
in white matter appearance . The myopathological mechanisms suggest that repeated cycles of myofiber
[5]
degeneration exhaust the regenerative capacity of muscle satellite cells and macrophages induce fibrotic
mechanisms, thereby causing progressive myofiber replacement with collagen. To counteract this, several
approaches have been attempted, including the recent use of givinostat.

Eteplirsen, an antisense-oligonucleotide drug that induces exon 51 skipping, is available on the market. A
recent study has shown improved overall survival among the majority of US patients receiving eteplirsen
[6]
since its approval, compared to a natural history cohort. Approximately 14% of DMD patients benefit from
eteplirsen.

Ataluren is used to overcome stop codon mutations in DMD, including in female carriers. Nonsense
mutations are present in about 14% of DMD cases. Ataluren (Translarna, PTC124) received conditional
marketing approval in 2014, though its use was discussed by the EMA.

Regarding gene therapy for DMD, one major challenge is that the full DMD gene is too large to fit into an
adeno-associated virus (AAV) vector, leading to the development of microdystrophin.

Fordadistrogene or movaparvovec is an investigational gene therapy utilizing a modified adeno-associated
virus serotype 9 (AAV9) capsid to deliver a shortened, but functional dystrophin (mini-dystrophin) under
the control of a human muscle-specific promoter. The virus is delivered into the blood via a single infusion.
This treatment aims to slow or halt DMD muscle degeneration. The CIFFREO trial randomly assigned 226
ambulatory boys (nearly 2/3 of the participants) on a stable corticosteroid regimen to receive the gene
therapy (at 200 trillion vector genomes per kg body weight) or a placebo. After a year, the boys who received
fordadistrogene movaparvovec would get the placebo and boys first given the placebo would receive the
gene therapy. The trial was paused following the sudden death of a boy who received the gene therapy.

The primary endpoint of the trial was to assess changes in motor skills using the North Star Ambulatory
Assessment total score after one year. However, neither the gene therapy nor placebo groups showed
statistically significant differences, nor did secondary endpoints such as the time needed for a 10-meter
walk/run and rising from the floor (Gowers’ sign).

Sarepta Therapeutics’ Delandistrogene moxeparvovec (SRP-9001), another adeno-associated virus gene
therapy designed to carry a “microdystrophin”, has been approved for the treatment of ambulatory pediatric
patients aged 4 through 5 years with DMD. However, continued approval is still to come, and pioneering
research is ongoing in dystrophic muscle, with further trials anticipated.