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Pharmacology of a Central Nervous System Delivered 2′-O-Methoxyethyl–Modified Survival of Motor Neuron Splicing Oligonucleotide in Mice and Nonhuman Primates
Open accessAbstract
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.
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“Many modifications can be applied to microRNA inhibitors and mimics, improving their stability, permeability, and specificity.”
From MiR-128-3p – a gray eminence of the human central nervous system (2024) · cites this paper as [195]
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“intrathecal ASO injection to nonhuman primates led to accumulation of ASO in the cortical neuronal and glial cells (Rigo et al., 2014).”
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“Notably, intrathecal antisense oligonucleotides (ASO) injection successfully delivered ASO to the cortical cells in nonhuman primates [142].”
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Metadata
- Authors
- 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.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- ORCID
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 350
- Issue
- 1
- Pages
- 46-55
- ISSN
- 0022-3565 (ISSN-L)
- PMC
- PMC4056267
- OpenAlex
- W2090804804
- Cited by
- 283
- References
- 56
- Citations by year
- 2026: 16 · 2025: 19 · 2024: 22 · 2023: 25 · 2022: 24 · 2021: 25 · 2020: 35 · 2019: 24 · 2018: 23 · 2017: 23 · 2016: 21 · 2015: 21 · 2014: 5
- FWCI
- 11.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- Spinal Muscular Atrophy Foundation
- National Institute of General Medical Sciences (R37-GM42699, R37GM042699, R01GM042699)
- Topics
- Health Sciences › Medicine › Genetics (clinical) › Neurogenetic and Muscular Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- spinal muscular atrophy, antisense oligonucleotides, SMN protein, central nervous system delivery, intrathecal administration, pharmacokinetics, pharmacodynamics, non-human primates, modified oligonucleotides, preclinical pharmacology
- MeSH terms
- Animals, Brain, Female, Injections, Intraventricular, Macaca fascicularis, Male, Muscular Atrophy, Spinal, Oligonucleotides, RNA Splicing, Mice, Knockout, Oligodeoxyribonucleotides, Antisense, Mice, Survival of Motor Neuron 2 Protein, Infusions, Intraventricular
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