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Drug transport across the blood-cerebrospinal fluid barrier

The effective administration of therapeutics into the central nervous system (CNS) is one of the greatest challenges in the treatment of CNS disorders, since highly selective semi-permeable barriers (the blood-brain barrier and the blood-cerebrospinal fluid barrier) restrict the access of therapeutics into the CNS. Despite concentrated efforts to understand and improve delivery into the CNS, little progress has been made in translating research into clinical interventions.

Fluorescence microscopic image of the basolateral localization of the ABC transporter ABCC1 (red) in an epithelial cell line of the choroid plexus. Apically located tight junctions (arrows) are identified by detection of ZO-1 (green), cell nuclei are stained with DAPI (blue).

Approaches to optimizing drug candidates

Agonists of the tumor necrosis factor (TNF) receptor 2 (TNFR2) can be used to treat CNS disorders. The project is part of a consortium that aims to minimize unwanted peripheral TNFR2 activation, improve CNS delivery and target neuroprotective bioactivity after delivery. In the present subproject, models of the blood-cerebrospinal fluid barrier are used to analyze the CNS transport of the biologicals under investigation in vitro. Using an endothelial cell line of the choroid plexus, an optimized two-cell type model system of the blood-cerebrospinal fluid barrier will be generated. Since CNS inflammatory states are a feature of many neurodegenerative diseases, these will be induced in the models and the effects on the transport of the biologicals will be analyzed.

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