Background: PepGen’s EDO cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides. Delivery of oligonucleotides to affected tissues is a major challenge that limits their efficacy. PGN-EDODM1 is being evaluated for the treatment of DM1. PGN-EDODM1 binds to the pathogenic trinucleotide repeat expansion in myotonic dystrophy protein kinase (Dmpk) mRNA and reduces sequestration of Muscleblind (MBNL) proteins within nuclear RNA foci through a steric blocking mechanism. Release of MBNL proteins is hypothesized to correct DM1 spliceopathy; a central cause of DM1.
Objectives: A nonclinical dataset, including in vitro and in vivo pharmacology studies, to support initiation of clinical studies of PGN-EDODM1.
Methods: In vitro studies: DM1 donor cells with 2,600 CTG repeats were treated with PGN EDODM1, and nuclear RNA foci profiles and splicing events were evaluated after 24 hours. In vivo studies: PGN-EDODM1 was administered intravenously to wildtype mice and DM1 mouse model HSALR (containing 250 CTG repeats in the HSA gene), and splicing events and myotonia were measured.
Results: PGN-EDODM1 administration resulted in a dose-dependent reduction in toxic RNA foci and correction of mis-splicing in cells. In the HSALR model, a single dose resulted in high muscle concentrations of PGN-EDODM1, dose-dependent correction of mis-splicing persisting over 24 weeks, and resolution of myotonia.
Conclusions: There are no approved therapies for DM1. PGN-EDODM1 shows considerable therapeutic potential. Nonclinical results support a Phase 1 single-ascending dose study (with an open-label extension) in adults with DM1 and will be initiated in 2023. Details of the clinical trial design will be presented.