Ruslan Rust receives SNF Spark Grant to develop a brain-shuttle for cell therapies

Drug delivery strategies to overcome the blood brain barrier included ultrasound, nanoparticles, or intranasal drug delivery and have all shown only very limited translational success; mainly due to the complex, multi-cellular BBB anatomy and specialized junctions. Here, we propose an alternative route of administration by bypassing the BBB through the choroidal plexus (CP), a single-cell-layer of ependymal cells separating the blood and cerebral spinal fluid (CSF) at the ventricles of the brain. There is increasing evidence for migration of immune cells including macrophages and T-cells across CP for immune surveillance, which is reinforced following brain injury e.g. after stroke. New trafficking pathways across the CP have been recently discovered that may function as a shuttle system for transplanted cells to enter the brain. In this project, we will express specific brain-shuttle-antigens on cells to reinforce paracellular migration to the brain. Engineered cells will be systemically infused in stroked, immunosuppressed mice and continuously tracked using in vivo bioluminescence imaging. Recovery of mice will be assessed through detailed kinematic functional testing based on deep neural networks (DeepLabCut). In order to assess high spatial distribution of the cells, whole brains will be cleared using CLARITY and imaged with single plane illumination microscopy (SPIM). Successful implication of the project can be directly transferred into clinical practice in optimizing efficacy of future cell-based therapies for stroke. Moreover, efficacy of cell therapies applied to other major neurological diseases may equally profit from the gained knowledge including acute injuries e.g. traumatic brain injury or spinal cord injury as well as chronic neurological disorders e.g. Parkinson’s Disease, Multiple Sclerosis, and Alzheimer’s Disease.

Gina Schifferle

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