Pharmacology, Biodistribution and Tolerability of a PATrOL™-Enabled Investigational Genetic Therapy for Myotonic Dystrophy, Type 1


Pre-Clinical Research

Poster Number: 120


Sandra Rojas-Caro, MD, Neubase Therapeutics, Renta Hutabarat, PhD, Neubase Therapeutics, Valentina Di Caro, PhD, Neubase Therapeutics, William Riedl, PhD, Neubase Therapeutics, Noel R Monks, PhD, Neubase Therapeutics, Nathan Tavenor, PhD, Neubase Therapeutics, Barry Badeau, PhD, Neubase Therapeutics, Jeremy Gleaton, PhD, Neubase Therapeutics, Ramesh Batwal, PhD, Neubase Therapeutics, Dani M Stoltzfus, PhD, Neubase Therapeutics, Anthony Rossomando, PhD, Neubase Therapeutics, William Mann, PhD, Neubase Therapeutics, Dietrich A Stephan, PhD, Neubase Therapeutics

Patients with myotonic dystrophy, type 1 (DM1) suffer from cognitive deficits and muscle pathology caused by a trinucleotide expansion in the DMPK gene. Initial studies of our novel delivery technology in transgenic animal models, have demonstrated pharmacological activity of the PATrOL™ platform-enabled peptide nucleic acid (PNA) pharmacophore in both brain and muscle after systemic administration. An exploratory radiolabeled biodistribution study of its delivery module administered intravenously in nonhuman primates showed distribution to brain, muscle, and heart, the major organs affected in DM1. To evaluate the capacity of our PATrOL™ DM1 lead candidate to correct the DM1 phenotype in vitro, we assessed knock down of the human DMPK transcript and correction of splicing defects in both fibroblasts and myoblast cultures derived from DM1 patients. Treatment with our DM1 lead candidate rapidly reduced the human DMPK transcript and corrected splicing defects at nanomolar concentrations. Molecular and functional pharmacological activity, tissue distribution and tolerability were evaluated in the HSA*LR mouse model following single and repeated subcutaneous, intravenous, and intramuscular administration. As with the in vitro results in DM1 patient-derived cell lines, treatment with our lead candidate rapidly reduced mutant transcript levels, corrected splicing defects and rescued myotonia in this mouse model. At well tolerated doses in rodents, the levels of our DM1 lead candidate in key target tissues were above those required to reverse splicing defects in vitro in patient cells. These encouraging preclinical data support the potential for our PATrOL™ DM1 lead candidate to be developed as a potential therapy for DM1 patients.