PGN-EDODM1: Preclinical Data Supporting the Development of an Enhanced Delivery Oligonucleotide (EDO) for the Treatment of Myotonic Dystrophy Type 1 (DM1)
Ashling Holland1, Arnaud Klein2, Caroline Godfrey1, Niels Svenstrup1, Jane Larkindale1, Sonia Bracegirdle1, Denis Furling2, Jaya Goyal1
1PepGen Inc., 2Sorbonne Université
Objective:
In vitro and in vivo evaluation of pharmacological activity via measurement of splicing changes, nuclear RNA foci, and myotonia.
Background:
PepGen’s EDO cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides. PGN-EDODM1 is being evaluated for the treatment of DM1. PGN-EDODM1 binds to the pathogenic CUG repeat expansion in 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.
Design/Methods:
DM1 donor cells with 2,600 CTG repeats were treated with PGN-EDODM1 (1, 2, 5, 10, or 20 µM). Nuclear RNA foci profiles and splicing events were evaluated after 24 hours.
PGN-EDODM1 (0, 10, 20, 30, and 50 mg/kg) was administered intravenously (IV) to wildtype (WT) or HSALR mice (DM1 murine model containing 250 CTG repeats in the HSA gene). Splicing profiles were evaluated in gastrocnemius and quadricep muscles 2-weeks post dose and myotonia was quantitatively assessed. Tissue levels of PGN-EDODM1 were analyzed.
To explore the duration of pharmacological activity, PGN-EDODM1 (30 mg/kg IV) was administered to WT and HSA
LR mice and splicing profiles were evaluated 12 or 24 weeks post-dose.
Results:
The cellular model showed dose-dependent reduction in toxic RNA foci and correction of mis-splicing. 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. PGN-EDODM1 was generally well tolerated at pharmacological doses.
Conclusions:
These preclinical studies demonstrate that PGN-EDODM1 reduced nuclear RNA foci and corrected mis-splicing at clinically relevant, tolerable doses with effects lasting up to 24 weeks. The HSALR mouse showed resolution of myotonia after a single PGN-EDODM1 dose. A Phase 1 clinical study in adults with DM1 will be initiated in 2023.