A PATrOL™- Enabled Investigational Genetic Therapy for DM1: Mouse Pharmacokinetics, Biodistribution, and CNS Penetration after Systemic Administration


Topic:

Pre-Clinical Research

Poster Number: 121

Author(s):

Sandra Rojas-Caro, MD, Neubase Therapeutics, Renta Hutabarat, PhD, Neubase Therapeutics, Eunah Cho, PhD, Neubase Therapeutics, Barry Badeau, PhD, Neubase Therapeutics, Dani M Stoltzfus, PhD, Neubase Therapeutics, Noel R Monks, PhD, Neubase Therapeutics, Anthony Rossomando, PhD, Neubase Therapeutics, William Mann, PhD, Neubase Therapeutics, Dietrich A Stephan, PhD, Neubase Therapeutics

Initial studies using a PATrOL™ platform-enabled peptide nucleic acid (PNA) pharmacophore combined with a novel delivery technology in transgenic animal models demonstrated pharmacologic activity in both brain and muscle following systemic administration. Patients with DM1 suffer from cognitive deficits and muscle pathology caused by a trinucleotide expansion in the DMPK gene. An exploratory radiolabeled biodistribution study of the delivery module administered intravenously in nonhuman primates showed distribution to brain, muscle, and heart, the major organs affected in DM1. A single dose of our PATrOL™ DM1 selected candidate was administered subcutaneously (10 or 30 mg/kg) or intravenously (30 mg/kg) in BALB/c mice to evaluate the pharmacokinetics and biodistribution and examine central nervous system (CNS) penetration. Blood and tissues were collected over a time course ranging from 0.5 hours to 28 days. Serum and tissue compound concentrations were quantified by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using Phoenix WinNonLin. Following subcutaneous administration, compound maximal plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-t) were approximately dose-proportional; bioavailability was ~46%. Plasma Cmax and AUC0-t after intravenous dosing were 2490 ng/mL and 8655 hours*ng/mL, respectively. Compound plasma total body clearance and volume of distribution following subcutaneous or intravenous administration were ?4-fold greater than mouse glomerular filtration rate (GFR) and ~110-fold greater than mouse blood volume, respectively, suggesting primarily GFR clearance and wide tissue distribution. Data will be presented supporting distribution of our investigational PNA therapy targeting DMPK pre-mRNA conjugated to a novel delivery technology to the brain and throughout the body following systemic administration in BALB/c mice, consistent with previously observed CNS pharmacologic activity.