Pharmacology of a central nervous system delivered 2′-O-methoxyethyl- modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates

Rigo, F., Chun, S. J., Norris, D. A., Hung, G., Lee, S., Matson, J., Fey, R. A., Gaus, H., Hua, Y., Grundy, J. S., Krainer, A. R., Henry, S. P., Bennett, C. F. (2014) Pharmacology of a central nervous system delivered 2′-O-methoxyethyl- modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates. Journal of Pharmacology and Experimental Therapeutics, 350 (1). pp. 46-55. ISSN 15210103

URL: http://www.ncbi.nlm.nih.gov/pubmed/24784568
DOI: 10.1124/jpet.113.21240

Abstract

Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by the loss of survival of motor neuron (SMN) protein. Previously, we demonstrated that ISIS 396443, an antisense oligonucleotide (ASO) targeted to the SMN2 pre-mRNA, is a potent inducer of SMN2 exon 7 inclusion and SMN protein expression, and improves function and survival of mild and severe SMA mouse models. Here, we demonstrate that ISIS 396443 is the most potent ASO in central nervous system (CNS) tissues of adult mice, compared with several other chemically modified ASOs. We evaluated methods of ISIS 396443 delivery to the CNS and characterized its pharmacokinetics and pharmacodynamics in rodents and nonhuman primates (NHPs). Intracerebroventricular bolus injection is a more efficient method of delivering ISIS 396443 to the CNS of rodents, compared with i.c.v. infusion. For both methods of delivery, the duration of ISIS 396443-mediated SMN2 splicing correction is long lasting, with maximal effects still observed 6 months after treatment discontinuation. Administration of ISIS 396443 to the CNS of NHPs by a single intrathecal bolus injection results in widespread distribution throughout the spinal cord. Based upon these preclinical studies, we have advanced ISIS 396443 into clinical development. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons > exon splicing
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > oligonucleotide
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > splicing factor
CSHL Authors:
Communities: CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
CSHL labs > Krainer lab
CSHL Cancer Center Shared Resources > Antibody and Phage Display Service
Depositing User: Matt Covey
Date Deposited: 18 Jul 2014 14:07
Last Modified: 30 Oct 2015 13:59
PMCID: PMC4056267
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30540

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