Duchenne muscular dystrophy (DMD) is a severe, progressive X-linked muscle degenerative disorder caused by nonsense or out-of-frame mutations in the DMD gene that result in the absence of functional dystrophin protein. Its absence leads to continuous muscle fibre damage during contraction, and muscle fibres are eventually replaced by fibrotic and adipose tissues. Histology of DMD muscle is characterized by centrally located myonuclei and variable muscle fibre sizes, both hallmarks of actively regenerating muscle. In addition, dystrophic muscle also presents interstitial inflammation due to myofibre necrosis. In contrast, milder Becker muscular dystrophy (BMD) is caused by in-frame mutations in the DMD gene which enable the expression of an internally truncated but partially functional protein. Therefore, a promising therapeutic strategy for DMD is to induce exon skipping using antisense oligonucleotides (AONs) in order to rescue the expression of an in-frame, partially truncated dystrophin protein. Phosporodiamidate morpholino oligomers (PMOs) are one of the most widely used AON chemistries. In fact, FDA has recently approved a PMO, Eteplirsen, for DMD treatment. One of the various obstacles that hindered the approval of this drug was the measurement of restored dystrophin expression, given its patchy distribution within the muscle tissue.
In previous investigations, this group tried to determine the underlying principle of dystrophin expression pattern. However, they found no evidence pointing towards an association between exon skipping efficacy and residual PMO concentration in muscle, or preference in the uptake of systemically delivered PMOs in terms of muscle groups or fibre types. Therefore, they hypothesized that other factors must exist that explain dystrophin distribution. Intravenously injected PMO remains in serum for less than 2h and its entry to the muscle fibers is limited, thus restricting its efficacy.
The main aim of the study was to determine the factors that have an effect on exon skipping efficacy in preclinical and clinical trials. They concluded that efficient systemic PMO delivery relies on PMO accumulation within inflammatory foci in regenerating dystrophic lesions and on fusion of PMO-loaded myoblasts into repairing myofibers. Furthermore, they claim that PMO is retained in inflammatory foci, that act as local PMO reservoirs, where it is internalized by macrophages, differentiating myoblasts and newly forming myotubes.