Background: PepGen’s enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular 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.
Objectives: In vitro and in vivo pharmacology studies to support PGN-EDODM1 clinical studies.
Design/Methods: PGN-EDODM1 pharmacology was characterized using DM1 patient derived myoblasts and the HSALR transgenic mouse model of DM1.
Results: Control and DM1 myoblasts were differentiated and treated with PGN-EDODM1, which resulted in dose-dependent reduction in pathogenic myonuclear foci, liberation of MBNL1 from foci, and correction of mis-splicing in DM1 cells, while DMPK levels remained unchanged. A single intravenous (IV) dose of PGN-EDODM1 administered to HSALR mice resulted in high muscle concentrations of PGN-EDODM1, resolution of myotonia and dose-dependent correction of mis-splicing when evaluated 2 weeks postdose. Splicing correction in HSALR mice persisted up to 24 weeks following a single dose. PGN-EDODM1 repeat-doses every 4 weeks administered in HSALR mice resulted in further improvement of DM1 pathology with high muscle concentrations, a dose-dependent increase in mis-splice correction, and resolution of myotonia.
Conclusions: Currently, there are no approved therapies for DM1. Nonclinical pharmacology studies with PGN-EDODM1 showed considerable therapeutic potential on splicing and myotonia correction. Nonclinical data warrants clinical evaluation in the Phase 1 single-ascending dose study FREEDOM-DM1 in adults with DM1.