PepGen’s enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and nuclear uptake of therapeutic oligonucleotides. Investigational PGN-EDODM1 is being evaluated for the treatment of myotonic dystrophy type 1 (DM1). PGN-EDODM1 is designed to bind pathogenic CUG trinucleotide repeat expansions in DMPK mRNA, thereby liberating MBNL1 protein through steric blocking and without degrading DMPK transcript. Liberation of sequestered MBNL1 is hypothesized to restore splicing profiles of multiple downstream transcripts; a central cause of DM1 pathology.
In vitro treatment of DM1 myotubes showed PGN-EDODM1 delivery to the nucleus, and treatment of DM1 patient myotubes with both short-CUG and long-CUG repeats demonstrated dose-dependent reduction of pathogenic myonuclear foci, liberation of MBNL1 from foci, and correction of mis-splicing without DMPK RNA degradation. A single intravenous (IV) dose of PGN-EDODM1 to HSALR mice resulted in dose-dependent correction of mis-splicing and improvement in myotonia. Following repeat-dosing of PGN-EDODM1 once every 4 weeks, near complete resolution of DM1 pathology including correction of mis-splicing and resolution of myotonia was observed.
Toxicology studies in NHPs indicate repeat dosing with PGN-EDODM1 was generally safe and well tolerated. No persistent elevation of kidney biomarkers was observed at doses through 60 mg/kg. Additionally, there were no adverse findings in the kidney after 4 monthly doses of 60 mg/kg, nor notable hematologic or hepatic or cardiovascular effects.
Currently, there are no approved therapies for DM1. Nonclinical pharmacology and safety studies with PGN-EDODM1 showed meaningful therapeutic potential on splicing correction and myotonia correction and support the ongoing Phase 1 single ascending dose study FREEDOM-DM1 and Phase 2 multiple ascending dose study FREEDOM2-DM1 in adults with DM1.