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Cited by 114RNA Interference and Gene DeliveryNeurogenetic and Muscular Disorders ResearchBarrier Structure and Function Studies

Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging

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Mazur, Curt, Powers, Berit, Zasadny, Kenneth, Sullivan, Jenna M., Dimant, Hemi, Kamme, Fredrik, Hesterman, Jacob, Matson, John +16 more·2019·JCI Insight
DOI 10.1172/jci.insight.129240PMC PMC6824309
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Abstract

Intrathecal (IT) delivery and pharmacology of antisense oligonucleotides (ASOs) for the CNS have been successfully developed to treat spinal muscular atrophy. However, ASO pharmacokinetic (PK) and pharmacodynamic (PD) properties remain poorly understood in the IT compartment. We applied multimodal imaging techniques to elucidate the IT PK and PD of unlabeled, radioactively labeled, or fluorescently labeled ASOs targeting ubiquitously expressed or neuron-specific RNAs. Following lumbar IT bolus injection in rats, all ASOs spread rostrally along the neuraxis, adhered to meninges, and were partially cleared to peripheral lymph nodes and kidneys. Rapid association with the pia and arterial walls preceded passage of ASOs across the glia limitans, along arterial intramural basement membranes, and along white-matter axonal bundles. Several neuronal and glial cell types accumulated ASOs over time, with evidence of probable glial accumulation preceding neuronal uptake. IT doses of anti- GluR1 and anti- Gabra1 ASOs markedly reduced the mRNA and protein levels of their respective neurotransmitter receptor protein targets by 2 weeks and anti- Gabra1 ASOs also reduced binding of the GABA A receptor PET ligand 18 F-flumazenil in the brain over 4 weeks. Our multimodal imaging approaches elucidate multiple transport routes underlying the CNS distribution, clearance, and efficacy of IT-dosed ASOs.

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Authors
Mazur, C., Powers, B., Zasadny, K., Sullivan, J. M., Dimant, H., Kamme, F., Hesterman, J., Matson, J., Oestergaard, M., Seaman, M., Holt, R. W., Qutaish, M., Polyak, I., Coelho, R., Gottumukkala, V., Gaut, C. M., Berridge, M., Albargothy, N. J., Kelly, L., Carare, R. O., Hoppin, J., Kordasiewicz, H., Swayze, E. E., & Verma, A.
Affiliations
  • Ionis Pharmaceuticals (United States) (US)
  • Invicro (United States) (US)
  • Biogen (United States) (US)
  • 3D Imaging, Little Rock, Arkansas, USA.
  • University of Southampton (GB)
Corresponding author
Mazur, Curt
ORCID
Venue
JCI Insight
Publisher
American Society for Clinical Investigation
Published
2019-10-17
Volume
4
Issue
20
ISSN
2379-3708 (ISSN-L)
DOI
10.1172/jci.insight.129240
PMC
PMC6824309
OpenAlex
W2980602575
Cited by
114
References
10
Citations by year
2026: 25 · 2025: 24 · 2024: 15 · 2023: 12 · 2022: 19 · 2021: 11 · 2020: 8
FWCI
3.14
Type
journal article
Language
en
Open access
Locations
  • JCI Insight (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Biogen (N/A)
  • Ionis Pharmaceuticals (N/A)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
spinal muscular atrophy, multimodal imaging, glia limitans, lymph node clearance, GABAA receptor, GluR1, axonal transport, glial uptake
MeSH terms
Intravital Microscopy, Single Photon Emission Computed Tomography Computed Tomography, Animals, Arteries, Brain, Flumazenil, Humans, Injections, Spinal, Male, Muscular Atrophy, Spinal, Neuroglia, Neurons, Pia Mater, Receptors, GABA-A, RNA, Messenger, Thionucleotides, Tissue Distribution, Oligonucleotides, Antisense, Receptors, AMPA, Rats, Gene Knockdown Techniques, GABA-A Receptor Antagonists, Molecular Targeted Therapy, Spatio-Temporal Analysis

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