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Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging
Curt Mazur, … , Eric E. Swayze, Ajay Verma
Curt Mazur, … , Eric E. Swayze, Ajay Verma
Published October 17, 2019
Citation Information: JCI Insight. 2019;4(20):e129240. https://doi.org/10.1172/jci.insight.129240.
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Research Article Neuroscience

Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging

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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 GABAA receptor PET ligand 18F-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.

Authors

Curt Mazur, Berit Powers, Kenneth Zasadny, Jenna M. Sullivan, Hemi Dimant, Fredrik Kamme, Jacob Hesterman, John Matson, Michael Oestergaard, Marc Seaman, Robert W. Holt, Mohammed Qutaish, Ildiko Polyak, Richard Coelho, Vijay Gottumukkala, Carolynn M. Gaut, Marc Berridge, Nazira J. Albargothy, Louise Kelly, Roxana O. Carare, Jack Hoppin, Holly Kordasiewicz, Eric E. Swayze, Ajay Verma

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Figure 3

ASO colocalization with axonal and glial structures.

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ASO colocalization with axonal and glial structures.
IHC performed for A...
IHC performed for ASO and GFAP at 30 minutes after lumbar IT dosing of anti-GluR1 ASOs. From left to right, staining is shown associated with lumbar spinal cord axonal bundles, axon- and astrocyte-rich sub-pial tissue in cerebral cortex, and the Bergmann glia-rich layers of the cerebellar cortex. Arrowheads show early ASO signal that was observed in what appear to be Bergman glial cell bodies adjacent to Purkinje cells, as stained by GFAP IHC in adjacent sections Images in the left 3 columns are at ×20 magnification and the right 2 images have additional ×2 digital magnification.

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