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Scherman. Rare Dis Orphan Drugs J 2023;2:12 https://dx.doi.org/10.20517/rdodj.2023.01 Page 15 of 35

Figure 7. Therapeutic exon skipping. An ASO targeting and blocking an intronic splice acceptor or donor site or an exonic splice
enhancer site enforces exon skipping. In the case of the picture, the ASO targets and binds to the acceptor site of intron N+1, resulting
in the skipping of ExonN+2. The exons N+1 and N+3 must be in frame to ensure the expression of a protein devoid of only exon N+2,
which might still be fully or partially functional.

Figure 8. A: Exons 43 to 53 of the integral dystrophin gene. B: In grey, the group of exons whose concomitant deletion could, in theory,
lead to a shortened functional or semi-functional dystrophin protein comprising only the protein encoded by the exons in blue, and
allowing to skip mutated Exon 51.

exons 53 and 45, and at present times, there are 4 ASOs on the market for DMD, all being morpholinos.
Other chemistries are in clinical development: 2’MOE-PS 20 mer ASO and peptide-conjugated ASO [88,89] .
The clinical results obtained with Etiplisiren and other exon 51, exon 53, or exon 45 exclusion drugs
(Golodirsen and Casimersen) have been reviewed recently .
[7,8]
Spinal muscular atrophy
Spinal muscular atrophy (SMA) is the second most common fatal, autosomal recessive disease of infants. It
is a rare neuromuscular disease affecting 1/6000 children and is characterized by progressive general muscle
waste. Spinal muscular atrophy is caused by mutations or deletions in the Survival Motoneuron 1 gene
(SMN1) [90,91] . The gene for SMA was mapped to chromosome 5q13 within the telomeric region. The 20 kb
gene encodes a 294 amino acids protein.

SMA occurs under different levels of severity. Less severe forms are classified as Type II, Type III, and Type
IV, based on age of onset and ultimate motor disability. The most severe form is Type I (Werdnig-
Hoffmann disease), which occurs in about 60% of the cases and is associated with quadriplegia, respiratory
muscle paralysis, and mortality shortly after birth. Werdnig-Hoffmann patients are never able to sit by
themselves and necessitate to be supported for their nutritional and ventilation function . SMA patients
[92]
who can sit but are unable to walk without help are classified as Type II. Milder type III SMA patients can
be able to sit and walk, but they lose the walking capacity in adulthood . Type IV patients have a normal
[93]