Pharmacokinetic and Pharmacodynamic Investigations of ION-353382, a Model Antisense Oligonucleotide: Using Alpha-2-Macroglobulin and Murinoglobulin Double-Knockout Mice
Publication: nucleic acid therapeutics
Volume 26, Issue Number 4
Abstract
To investigate the pharmacokinetics (PKs) and pharmacodynamics (PDs) for ION-353382, an antisense oligonucleotide (ASO) targeting scavenger receptor class B type I (SRB1) mRNA, using alpha-2-macroglobulin (A2M), murinoglobulin double-knockout (DKO), and wild-type mice. Wild-type and DKO homozygous mice were administered a single subcutaneous injection of ION-353382 at 0, 5, 15, 30, and 60 mg/kg. Mice were sacrificed at 72 h with plasma and organs harvested. Both liquid chromatography–mass spectrometry (LC-MS) and enzyme-linked immunosorbent assay (ELISA) were used to determine ASO exposure with real-time PCR for SRB1 expression. Immunohistochemistry was evaluated to explore hepatic uptake of ASOs. The total plasma protein binding and profiling was assessed. Finally, two-dimensional gel electrophoresis identified protein expression differences. PK exposures were comparable between wild-type and DKO mice in plasma, liver, and kidney, yet a near twofold reduction in EC50 was revealed for DKO mice based on an inhibitory effect liver exposure response model. Total plasma protein binding and profiling revealed no major dissimilarities between both groups. Plasma proteome fingerprinting confirmed protein expression variations related to A2M. Histological examination revealed enhanced ASO distribution into hepatocytes and less nonparenchymal uptake for DKO mice compared to wild-type mice. Knocking out A2M showed improved PD activities without an effect on total plasma and tissue exposure kinetics. Binding to A2M could mediate ASOs to nonproductive compartments, and thus, decreased binding of ASOs to A2M could potentially improve ASO pharmacology.
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Information & Authors
Information
Published In
Copyright
Copyright 2016, Mary Ann Liebert, Inc.
History
Published in print: August 2016
Published online: 1 August 2016
Published ahead of print: 31 March 2016
Accepted: 3 March 2016
Received: 2 February 2016
Topics
- Animal models
- Antisense oligonucleotides
- Biomedical science, research and development
- DNA-based therapeutics
- Gene therapy
- Genetic Engineering, Biotechnology, and Regenerative medicine
- Monoclonal antibody research
- Monoclonal antibody therapy
- Nucleic acid therapeutics
- Nucleosides
- Oligonucleotides/DNA antisense therapy
- Research methodology
Authors
Author Disclosure Statement
All authors are employees of Ionis Pharmaceuticals, Carlsbad, California.
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