Myotonic dystrophy type 1 (DM1) is a hereditary progressive multisystemic neuromuscular disease encompassing a wide variety of pathologies including myotonia, cardiac complications, cataracts, insulin sensitivity and central nervous system defects. DM1 is caused by a trinucleotide repeat expansion in the 5’ untranslated region of the DMPK gene. This CUG repeat forms a stable hairpin loop that sequesters the splicing factor muscleblind-like protein 1 (MBNL1), which is required for the processing of a number of RNA transcripts.
A variety of nucleic acid approaches have been developed for DM1 including those targeting the knockdown of the DMPK RNA and those adopting a steric blocking modality. These approaches have historically been hindered by limitations in the efficiency of nucleic acid delivery to affected tissues.
Through the rational development of innovative enhanced delivery oligonucleotides (EDOs), PepGen has addressed the challenge of delivery to cardiac and skeletal muscle cells. PepGen has developed PGN-EDODM1, a peptide conjugated oligonucleotide that hybridises to the CUG repeat and blocks the interaction of MBNL1 with the toxic hairpin loops. In the HSA-LR murine DM1 model we have demonstrated that our lead candidate, PGN-EDODM1 shows impressive, sustained correction of downstream mis-splicing events implicated in DM1, along with the complete amelioration of the myotonia phenotype following a single low dose administration. These results underline the potential of this therapeutic as a competitive, disease-modifying treatment for DM1.