Unlocking the potential of oligonucleotide therapeutics for Duchenne muscular dystrophy through enhanced delivery


Pre-Clinical Research

Poster Number: 129


James McArthur, PhD, PepGen

Exon skipping therapeutic oligonucleotides are precision medicines designed to modulate the genetic machinery, which show great promise in treating genetic disorders such as Duchenne muscular dystrophy (DMD). Such oligonucleotides can be utilized to skip over DMD-causing mutations and restore the reading frame of the dystrophin transcript to produce a truncated dystrophin protein similar to protein produced by people with the less severe dystrophinopathy, Becker muscular dystrophy. Four exon skipping oligonucleotides have been approved by the FDA to treat DMD – eteplirsen that skips exon 51, golodirsen and viltolarsen that skip exon 53 and casimersen that skips exon 45. However, while these treatments have demonstrated the ability to increase dystrophin levels, the maximal level of restored dystrophin remains very low compared to unaffected individuals (1 – 8% normal levels in skeletal muscle).

On their own, oligonucleotide therapeutics are not readily distributed to heart and skeletal muscle, the key tissues affected in neuromuscular diseases, and are not efficiently taken up into these cells. This results in the low levels of dystrophin produced by approved therapies. PepGen has addressed this delivery challenge through the rational development of enhanced delivery oligonucleotides (EDOs) that efficiently and effectively deliver oligonucleotides to skeletal, smooth and cardiac muscle. In both mice and non-human primates (NHPs), EDO treatment results in exon skipping at absolute doses as low as 5 mg/kg (mice) and 10 mg/kg (NHP) in skeletal muscles. NHP pharmacology studies showed that single doses of PGN-EDO51 also resulted in high levels of exon 51 skipping in smooth muscles, diaphragm and in the heart. Repeat dose studies in NHPs showed significant dose dependent increase in oligonucleotide and in exon skipping in skeletal muscles and cardiac tissue. PGN-EDO51 was well tolerated at target doses, and clinical trial enabling toxicology studies have been completed. The activity and tolerability of our approach demonstrated by the totality of studies to date provides strong support for the advancement of our lead candidate into initial clinical trials in early 2022. Updates on the clinical development for PGN-EDO51 will be discussed.