Project

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Brain shuttle for systemic delivery of iPS-derived neural cells in stroked mice

Applicant Rust Ruslan
Number 195902
Funding scheme Spark
Research institution
Institution of higher education University of Zurich - ZH
Main discipline Neurophysiology and Brain Research
Start/End 01.04.2021 - 31.07.2022
Approved amount 100'000.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Molecular Biology

Keywords (6)

brain shuttle; drug delivery; translational medicine; cell therapy; neuroscience; stroke

Lay Summary (German)

Lead
Die therapeutischen Optionen für Schlaganfallpatienten sind derzeit begrenzt. Eine vielversprechende experimentelle Strategie die Regenerationsfähigkeit des Gehirns nach einem Infarkt zu verbessern ist die Zelltherapie. In diesem Projekt, testen wir die Möglichkeit eines “Brain-Shuttle-Systems” um die Migration der transplantierten Zellen in die verletzten Hirnregionen zu begünstigen.
Lay summary
Jährlich erleiden 15 Millionen Menschen weltweit einen Schlaganfall. Ein Drittel der Patienten ist  dauerhaft auf fremde Hilfe angewiesen und leidet unter bleibenden Behinderungen. Die therapeutischen Möglichkeiten für Schlaganfallpatienten sind derzeit begrenzt und fokussieren sich ausschliesslich auf akute Rekanalisationstherapien. Eine experimentelle Strategie die Regenerationsfähigkeit des Gehirns zu verbessern ist die Zelltherapie. Obwohl Zelltherapien vielversprechende Resultate in Tiermodellen gezeigt haben, konnten diese Erkenntnisse bislang nur bedingt in klinischen Studien auf den Menschen übertragen werden. Ein wichtiger limitierender Faktor ist die zielgenaue Transplantation der Zellen in die Schlaganfallregion. Die Blut-Hirn-Schranke stellt dabei eine Barriere, die das erfolgreiche Eindringen der Zellen deutlich erschwert. Als Konsequenz erreicht nur ca. 1% der ursprünglich injizierten Zellen die verletzten Hirnregionen. In diesem Projekt statten wir die Zellen mit einem genetischen “Brain-Shuttle-System” aus, um die Migration der Zellen in das Gehirn zu begünstigen. Die Erkenntnisse aus diesem Projekt werden helfen das Eindringen der transplantierten Zellen in das Gehirn zu verstehen und eine verbesserte Zelltherapie zu entwickeln. 
 
Direct link to Lay Summary Last update: 02.03.2021

Responsible applicant and co-applicants

Abstract

Each year 5 million people remain permanently disabled after a stroke. The dramatic disability rate has not only a tremendous social and emotional impact but also huge consequences for healthcare costs with increasing tendency. This is largely due to the lack of effective medical therapy that promotes long-term recovery after stroke outside the confines of conventional treatments. Cell-based therapies have shown promising preclinical results in animal stroke models enabling functional recovery. However, these results have not been clearly confirmed in a clinical setting. A major limitation is the homing of the transplanted cells to the injury sites. Although many strokes are associated with the disruption of the blood-brain-barrier (BBB), only <1% of systemically injected cells reach the injured brain regions. Systemic injections are still the preferred route of administration in clinical trials, especially as local cell transplantations to the brain are very invasive and pose a risk of infection. 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. Transplanted cells within the CSF have been shown to efficiently migrate towards the site of injury following stroke. We have previously engineered GMP-compliant neural progenitor cells with a lentivirus construct to specifically express different proteins at the surface together with fluorescent and bioluminescent reporters. 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.
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