Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain
Benjamin A. Plog, Humberto Mestre, Genaro E. Olveda, Amanda M. Sweeney, H. Mark Kenney, Alexander Cove, Kosha Y. Dholakia, Jeffrey Tithof, Thomas D. Nevins, Iben Lundgaard, Ting Du, Douglas H. Kelley, and Maiken Nedergaard
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First published December 6, 2018 - More info
JCI Insight. 2018;3(23):e126138. https://doi.org/10.1172/jci.insight.126138.
Copyright © 2018, American Society for Clinical Investigation
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Abstract
Despite the initial promise of immunotherapy for CNS disease, multiple recent clinical trials have failed. This may be due in part to characteristically low penetration of antibodies to cerebrospinal fluid (CSF) and brain parenchyma, resulting in poor target engagement. We here utilized transcranial macroscopic imaging to noninvasively evaluate in vivo delivery pathways of CSF fluorescent tracers. Tracers in CSF proved to be distributed through a brain-wide network of periarterial spaces, previously denoted as the glymphatic system. CSF tracer entry was enhanced approximately 3-fold by increasing plasma osmolality without disruption of the blood-brain barrier. Further, plasma hyperosmolality overrode the inhibition of glymphatic transport that characterizes the awake state and reversed glymphatic suppression in a mouse model of Alzheimer’s disease. Plasma hyperosmolality enhanced the delivery of an amyloid-β (Aβ) antibody, obtaining a 5-fold increase in antibody binding to Aβ plaques. Thus, manipulation of glymphatic activity may represent a novel strategy for improving penetration of therapeutic antibodies to the CNS.
Authors
Benjamin A. Plog, Humberto Mestre, Genaro E. Olveda, Amanda M. Sweeney, H. Mark Kenney, Alexander Cove, Kosha Y. Dholakia, Jeffrey Tithof, Thomas D. Nevins, Iben Lundgaard, Ting Du, Douglas H. Kelley, Maiken Nedergaard
Original citation: JCI Insight. 2018;3(20):e120922. https://doi.org/10.1172/jci.insight.120922
Citation for this corrigendum: JCI Insight. 2018;3(23):e126138. https://doi.org/10.1172/jci.insight.126138
The molarity of the isotonic saline solution used was reported incorrectly in Figure 2A, Figure 3A, Figure 4B, the Methods section, and Supplemental Figure 7A. The correct molarity is 0.154 M. The correct sentence in Methods and the correct figure panels are below. The supplemental file has been updated.
The authors regret the errors.
