Duchenne muscular dystrophy, a progressive condition that affects both skeletal and cardiac muscle, is one of the most common genetic diseases. Almost 25 years after the discovery of the dystrophin gene, the first generation of antisense oligonucleotides (AONs) has entered clinical trials to target post-transcriptional control mechanisms and improve dystrophin expression and function.
The next generation of AONs have been covalently combined with cell-penetrating peptides (CPP) to target the AON to the appropriate tissue and facilitate transport across the cell membrane, however the relative targeting efficiencies of different CPPs are hard to evaluate in vivo. The primary outcome measure for the efficacy of these compounds is dystrophin restoration, which cannot address bio-distribution since dystrophin is only expressed in a limited subset of tissues. This limitation directly impacts the development of novel AON formulations, notably peptide-conjugated PMOs (PPMOs) which may have strongly divergent tissue targeting properties, both from PMOs and between PPMOs with different peptide sequences.
Our experiments aim to develop novel assays for the levels of these compounds in pre-clinical models. By measuring the rate at which they distribute to muscle tissue we aim to facilitate the development of advanced therapies and advance clinical trials for muscular dystrophies.