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Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging.
JCI Insight 2019; 4(20)JI

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+Show Affiliations

Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.Invicro, LLC, Boston, Massachusetts, USA.Invicro, LLC, Boston, Massachusetts, USA. Biogen, Cambridge, Masschusetts, USA.Invicro, LLC, Boston, Massachusetts, USA.Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.Invicro, LLC, Boston, Massachusetts, USA.Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.Invicro, LLC, Boston, Massachusetts, USA.Invicro, LLC, Boston, Massachusetts, USA.Invicro, LLC, Boston, Massachusetts, USA.Invicro, LLC, Boston, Massachusetts, USA.Invicro, LLC, Boston, Massachusetts, USA.Invicro, LLC, Boston, Massachusetts, USA.Invicro, LLC, Boston, Massachusetts, USA.3D Imaging, Little Rock, Arkansas, USA.University of Southampton, Hampshire, United Kingdom.University of Southampton, Hampshire, United Kingdom.University of Southampton, Hampshire, United Kingdom.Invicro, LLC, Boston, Massachusetts, USA.Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.Biogen, Cambridge, Masschusetts, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31619586

Citation

Mazur, Curt, et al. "Brain Pharmacology of Intrathecal Antisense Oligonucleotides Revealed Through Multimodal Imaging." JCI Insight, vol. 4, no. 20, 2019.
Mazur C, Powers B, Zasadny K, et al. Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging. JCI Insight. 2019;4(20).
Mazur, C., Powers, B., Zasadny, K., Sullivan, J. M., Dimant, H., Kamme, F., ... Verma, A. (2019). Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging. JCI Insight, 4(20), doi:10.1172/jci.insight.129240.
Mazur C, et al. Brain Pharmacology of Intrathecal Antisense Oligonucleotides Revealed Through Multimodal Imaging. JCI Insight. 2019 Oct 17;4(20) PubMed PMID: 31619586.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging. AU - Mazur,Curt, AU - Powers,Berit, AU - Zasadny,Kenneth, AU - Sullivan,Jenna M, AU - Dimant,Hemi, AU - Kamme,Fredrik, AU - Hesterman,Jacob, AU - Matson,John, AU - Oestergaard,Michael, AU - Seaman,Marc, AU - Holt,Robert W, AU - Qutaish,Mohammed, AU - Polyak,Ildiko, AU - Coelho,Richard, AU - Gottumukkala,Vijay, AU - Gaut,Carolynn M, AU - Berridge,Marc, AU - Albargothy,Nazira J, AU - Kelly,Louise, AU - Carare,Roxana O, AU - Hoppin,Jack, AU - Kordasiewicz,Holly, AU - Swayze,Eric E, AU - Verma,Ajay, Y1 - 2019/10/17/ PY - 2019/04/04/received PY - 2019/09/11/accepted PY - 2019/10/18/entrez PY - 2019/10/18/pubmed PY - 2019/10/18/medline KW - Neuroimaging KW - Neuroscience KW - Pharmacology JF - JCI insight JO - JCI Insight VL - 4 IS - 20 N2 - 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. SN - 2379-3708 UR - https://www.unboundmedicine.com/medline/citation/31619586/Brain_pharmacology_of_intrathecal_antisense_oligonucleotides_revealed_through_multimodal_imaging L2 - https://doi.org/10.1172/jci.insight.129240 DB - PRIME DP - Unbound Medicine ER -