Intrathecal antibody distribution in the rat brain: surface diffusion, perivascular transport and osmotic enhancement of delivery
Open accessAbstract
Key points It is unclear precisely how macromolecules (e.g. endogenous proteins and exogenous immunotherapeutics) access brain tissue from the cerebrospinal fluid (CSF). We show that transport at the brain-CSF interface involves a balance between Fickian diffusion in the extracellular spaces at the brain surface and convective transport in perivascular spaces of cerebral blood vessels. Intrathecally-infused antibodies exhibited size-dependent access to the perivascular spaces and tunica media basement membranes of leptomeningeal arteries. Perivascular access and distribution of full-length IgG could be enhanced by intrathecal co-infusion of hyperosmolar mannitol. Pores or stomata present on CSF-facing leptomeningeal cells ensheathing blood vessels in the subarachnoid space may provide unique entry sites into the perivascular spaces from the CSF. These results illuminate new mechanisms likely to govern antibody trafficking at the brain-CSF interface with relevance for immune surveillance in the healthy brain and insights into the distribution of therapeutic antibodies. Abstract The precise mechanisms governing the central distribution of macromolecules from the cerebrospinal fluid (CSF) to the brain and spinal cord remain poorly understood, despite their importance for physiological processes such as antibody trafficking for central immune surveillance, as well as several ongoing intrathecal clinical trials. In the present study, we clarify how IgG and smaller single-domain an…
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Compounds that traverse the barriers to the parenchyma typically only diffuse into superficial brain structures, and diffusional transport alone is not efficient for delivery over the long distances needed to reach deeper brain structures such as the striatum.
“If therapeutics do traverse these barriers to reach the parenchyma, compounds typically only diffuse into superficial brain structures, and diffusional transport alone is not efficient for delivery over the long distances needed to reach deeper brain structures such as the striatum.8”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [8]
Perivascular transport has been investigated for antibody-based therapies and ASOs but not for siRNA.
“While perivascular transport has been investigated for antibody-based therapies8 and ASOs,17 it has not been examined for siRNA.”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [8]
Single domain antibody constructs exhibit greater perivascular delivery relative to full length antibodies.
“For antibodies, single domain constructs exhibit greater perivascular delivery relative to full length antibodies.8”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [8]
CSF to brain delivery is driven by a combination of diffusion from subarachnoid/ventricular CSF and convective movement along CSF-filled perivascular spaces.
“CSF to brain delivery is driven by a combination of diffusion from subarachnoid/ventricular CSF and convective movement along CSF-filled perivascular spaces.8”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [8]
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- Authors
- Pizzo, M. E., Wolak, D. J., Kumar, N. N., Brunette, E., Brunnquell, C. L., Hannocks, M., Abbott, N. J., Meyerand, M. E., Sorokin, L., Stanimirovic, D. B., & Thorne, R. G.
- Affiliations
- University of Wisconsin–Madison (US)
- National Research Council Canada (CA)
- University of Münster (DE)
- King's College London (GB)
- Corresponding author
- Thorne, Robert G.
- ORCID
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2017-12-18
- Volume
- 596
- Issue
- 3
- Pages
- 445-475
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC5792566
- OpenAlex
- W2760852110
- Cited by
- 272
- References
- 19
- Citations by year
- 2026: 14 · 2025: 25 · 2024: 34 · 2023: 29 · 2022: 42 · 2021: 35 · 2020: 40 · 2019: 29 · 2018: 22 · 2017: 2
- FWCI
- 12.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- NPARC (submittedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Funders
- National Center for Advancing Translational Sciences (UL1TR000427, KL2TR00428)
- Deutsche Forschungsgemeinschaft (EXC 1003)
- National Science Foundation (DGE‐1256259)
- National Institutes of Health (T32 EBO11434)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- cerebrospinal fluid, surface diffusion, IgG, nanobodies, mannitol, leptomeningeal arteries, basement membrane, subarachnoid space, size-dependent transport, 3D MRI, rat brain
- MeSH terms
- Animals, Biological Transport, Biological Transport, Active, Blood-Brain Barrier, Brain, Diffusion, Extracellular Space, Female, Immunoglobulin G, Injections, Spinal, Osmosis, Tissue Distribution, Drug Delivery Systems, Rats, Sprague-Dawley, Rats, Single-Chain Antibodies, Optical Imaging
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