In late 2016, a 30-nucleotide PMO for exon 51 skipping, called Eteplirsen was conditionally
approved by the FDA. Its efficacy has remained debatable. Systemic delivery of Eteplirsen
to DMD patients had shown a dose-dependent response but with high variability in dystrophin
expression (Cirak et al., 2011). We investigated the influence of myofibre regeneration
on exon skipping by treating dystrophin-null mdx mice with labelled-PMOs together
with timed pulses of BrdU. This enabled us to define the stage of regeneration, relative
to systemic drug delivery, that coincides with optimal PMO uptake. PMO accumulation
was exclusive to inflamed regions where it entered inflammatory cells and newly forming
myotubes. We concluded much of the variability in PMO-induced dystrophin expression
reflects the favourable PMO uptake into inflamed and regenerating muscle regions.
The uptake mechanism is based on the fusion of PMO-loaded myoblasts into the newly
repairing segments of muscle fibres (Novak et al., 2017).
Next, we designed shorter 25-mer PMOs directed to the same Eteplirsen-targeted pre-mRNA
region and compared their efficacies in vitro and in vivo in the mdx52 murine model.
Our results showed that skipped-dystrophin induction was comparable between the 30-mer
PMO sequence of Eteplirsen and one of the shorter PMOs, while the other 25-mer PMOs
showed lower exon-skipping efficacies. Shorter PMOs would make higher doses economically
feasible, and high dosing would result in better drug uptake into muscle, induce higher
levels of dystrophin restoration in DMD muscle, and, increase the clinical efficacy
(Akpulat et al., 2018).
Literature:
Cirak et al., 2011, The Lancet; Novak et al., 2017 Nature Communication; Akpulat et
al., 2018 Molecular Therapy Nucleic Acids
