Abstract Details

Title Pharmacokinetics, Biodistribution, and Exploration of the Mechanism of Central Nervous System Penetration of a PATrOL™-Enabled Investigational Genetic Therapy for Myotonic Dystrophy, Type 1 after a Single Subcutaneous or Intravenous Administration in the BALB/c Murine Model

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P12 - Poster Session 12 (5:30 PM-6:30 PM)

Poster/Presentation
Number 11-004

Background Initial studies of a novel delivery technology in transgenic animal models demonstrated pharmacologic activity of the PATrOL™ platform-enabled peptide nucleic acid (PNA) pharmacophore in brain and muscle after 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.

Objective To evaluate the pharmacokinetics and biodistribution and explore the mechanism of central nervous system (CNS) penetration of an investigational genetic therapy for myotonic dystrophy, type 1 (DM1) following single subcutaneous or intravenous administration in BALB/c mice.

Design/Methods A single dose of investigational therapy compound was administered subcutaneously (10 or 30 mg/kg) or intravenously (30 mg/kg) to BALB/c mice. Blood and tissues were collected 0.5 hours to 28 days postdose. Serum and tissue compound concentrations were quantified by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using Phoenix WinNonLin.

Results Following subcutaneous administration, compound maximal plasma concentration (C_max) and area under the plasma concentration-time curve (AUC_0-t) were approximately dose-proportional; bioavailability was ~46%. Plasma C_max and AUC_0-t after intravenous dosing were 2490 ng/mL and8655 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. Compound distribution to brain, muscle, and other tissues, and mechanistic data, will be presented.

Conclusions 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.

Authors/Disclosures
Barry A. Badeau, PhD (NeuBase Therapeutics) PRESENTER	Dr. Badeau has received personal compensation for serving as an employee of NeuBase Therapeutics.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Dietrich A. Stephan, PhD (NeuBase Therapeutics)	Dr. Stephan has received personal compensation for serving as an employee of NeuBase Therapeutics, Inc.. Dr. Stephan has received stock or an ownership interest from Peptilogics, Inc.. Dr. Stephan has received stock or an ownership interest from Sharp Edge Labs, Inc.. Dr. Stephan has received stock or an ownership interest from Pendulum Therapeutics, Inc.. Dr. Stephan has received stock or an ownership interest from FarmaceuticalRx.
Sandra Rojas-Caro, MD (Neubase Therapeutics)	Dr. Rojas-Caro has received personal compensation for serving as an employee of Gemini Therapeutics. Dr. Rojas-Caro has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for HemoShear Therapeutics. Dr. Rojas-Caro has stock in Neubase Therapeutics.