Abstract Details

Title PGN-EDODM1: Preclinical Data Supporting the Development of an Enhanced Delivery Oligonucleotide (EDO) for the Treatment of Myotonic Dystrophy Type 1 (DM1)

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S48 - Therapeutics for Muscle Disease (3:30 PM-3:42 PM)

Poster/Presentation
Number 001

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 HSA^LR 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 HSA^LR 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 HSA^LR 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.

Authors/Disclosures
Ashling Holland, PhD (PepGen) PRESENTER	Dr. Holland has received personal compensation for serving as an employee of PepGen Inc.. Dr. Holland has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Jane Larkindale, PhD (Muscular Dystrophy Association)	Dr. Larkindale has received personal compensation for serving as an employee of PepGen.
	No disclosure on file
	No disclosure on file
	No disclosure on file

��ɫ��

��ɫ��