About this Research Topic

Background

The central nervous system is protected and supported by brain barriers, including the blood-brain barrier, blood-CSF barriers, tanycytic barriers of the circumventricular organs, and others. Vesicular transport is a predominant mechanism by which substances cross brain barriers, via processes such as receptor-mediated and adsorptive transcytosis. Transcytotic pathways have been leveraged for the delivery of therapeutic molecules to the CNS; for example, many antibodies and biologics in development bind the transferrin receptor to improve brain delivery through receptor-mediated transcytosis. The regulation of vesicular formation and trafficking within barrier cells is complex and often involves the coordinated activities of membrane transporter proteins, adaptor proteins and subcellular organelles such as the cytoskeleton and endo-lysosomal system. Trafficking of vesicles within the cell determines whether their cargo is shuttled into the CNS intact, recycled, or routed for degradation. This thematic issue presents recent advances on topics of vesicular transport in brain barrier cells and explores the application of these advances to CNS drug delivery.

Our current understanding of the regulation of vesicular pathways at brain barriers is limited and largely based on findings in other cell types such as epithelial cells. However, advances in molecular tools that can label components of endocytic and transcytotic machinery, as well as microscopic techniques that facilitate visualization at high-resolution will enhance the ability to observe vesicular trafficking within barrier cells in real-time. The use of improved in vitro barrier cell models and methods to visualize vesicular trafficking in vivo will also provide insight on vesicular trafficking within these unique cell types. Advancements in quantifying the biophysical characteristics of membranes, such as cell surface charge, could inform initial events that facilitate molecular interactions with barrier cells. Another emerging concept is that the extracellular matrix contributes to brain barrier functions; indeed, future studies are needed to understand how components of the extracellular matrix, such as proteoglycans and glycoproteins, regulate vesicular transport at brain barriers. Approaches that optimize the design of biologics that target known transporter systems, as well as those that aim to discover and characterize new transporters could provide improved strategies for drug delivery to the CNS.

We welcome submissions of original research, review and mini-reviews articles that focus on endocytic/transcytotic mechanisms of transport across brain endothelial cells, choroid plexus epithelial cells, and other brain barrier cells. Topics of special interest include, but are not limited to, the following:
• Mechanisms and regulation of endocytic/transcytotic pathways at brain barriers
• Transcytotic delivery of antibodies and other biologics to the brain
• Novel transcytotic receptors/delivery mechanisms at brain barriers
• Cell surface charge interactions with brain barrier cells
• Therapies targeting endocytosis/transcytosis
• Regulation of endocytosis and transcytosis by brain barrier extracellular matrices
• New methods and/or strategies for studying endocytic/transcytotic pathways at brain barriers

Topic editor R. Thorne is employed by Denali Therapeutics, Inc., a commercial company involved in, among other topics, the engineering of transport vehicles for the delivery of macromolecules, including antibody transport vehicles, into the central nervous system from the bloodstream. All other Topic Editors declare no competing interests with regards to the Research Topic subject.

Image credits: Meredith Calvert, Michelle Pizzo, Sarah DeVos, Robert Thorne and Joy Zuchero, Denali Therapeutics
Title: Transferrin receptor-mediated targeting drives intraneuronal uptake of anti-BACE via an antibody transport vehicle in vivo
Description: Volume rendered projection of super-resolution confocal z-stack of a region acquired within the hippocampus from a section of mouse brain, harvested 24 hours following injection with a transferrin-receptor targeted antibody transport vehicle (ATV). Uptake of the ATV into both neurons and the brain endothelial cells is visualized by staining with anti-huIgG (magenta, left; red, right); neurons are labeled with NeuN (cyan) and nuclei are stained with DAPI (yellow). Image stack was captured on Leica SP8 scanning confocal microscopy with a 100x/1.4 oil immersion objective and processed with Lightning super-resolution processing using the adaptive strategy algorithm.

Keywords: Endocytosis, Transcytosis, Antibodies, Biologics, Extracellular Matrix, Cell Surface Charge

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