Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disorder that occurs in 1 in 3,500 live male births. Mutations in the DMD gene result in the absence of dystrophin, a critical muscle protein, which leads to cell death, atrophy and progressive muscle degeneration. DMD sufferers experience progressive deterioration in physical abilities from birth onwards, with most boys requiring the use of a wheelchair by their early teens. Cardiomyopathies become increasingly common as the disease evolves, and recent studies have shown the majority of patients will die from cardiac complications.
Exon skipping therapeutic oligonucleotides are precision medicines capable of modulating genetic machinery, and show great promise in treating monogenic disorders like DMD. However, oligonucleotides delivered systemically demonstrate poor cell penetrance to skeletal and particularly cardiac muscles. PepGen has addressed this delivery challenge, through the rational development of enhanced delivery oligonucleotides (EDOs). PepGen's technology platform, underpinned by a substantial body of work validating our lead DMD candidate in multiple murine and NHP studies has demonstrated excellent delivery and pharmacological activity in critical tissues, including skeletal, cardiac and smooth muscle. A single administration of PepGen’s EDO technology to wild type and disease model mice achieved high levels of exon skipping in key tissue types with a single low dose. Wild type non-human primate pharmacology studies demonstrated that a single dose of PGN-EDO51 was well tolerated and resulted in exon 51 skipping levels of 74% in the tibialis anterior and 33% in the heart. The efficacy and safety of our approach provides strong support for the advancement of our lead candidate into the clinic.