Validation in Human(ized) Model Systems
Properly skilled and trained research professionals are paramount to stimulate ongoing innovations in viral vector-based gene therapy development, and to ensure their effective implementation in industrial and clinical settings. As explained below, each Doctoral Candidate (DC) has a specific assignment with a dedicated focus.
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In GET-IN WP3, we explore the human organ-on-chip (OoC) approach. OoC integrates microscale human tissues (with various cell types) in a microfabricated fluidic environment that captures complex multicellular characteristics, supports a continuous vasculature-like perfusion and recreates physiological stimuli. We will apply OoC to study individual gene therapy delivery routes, tissue-specific mechanisms of action and safety aspects.
Organ-on-Chip (OoC) technology employs microscale human tissues embedded in a microfluidic environment. OoC technology allows to study individual drug delivery routes and tissue specific mode of action and toxicity. DC4 will establish a pipeline for gene therapy delivery screening in OoCs using first exposure organs, and demonstrate live imaging of delivery routes using vector tool encoding for fluorescent proteins. On-target and off-target immune reactions will be assessed. The resulting platform will be available for evaluation by other DCs. In parallel, DC10 will combine OoC technology with existing primary airway on-chip models to obtain an innovative platform that can contribute to better predicting toxicities of rAAV- and VLP-based gene therapies for lung diseases. DC10 will extend the current model, by adding tissue resident macrophages, and PBMCs perfused via the vasculature. Inflammatory triggers and/or damage to lung epithelium will elicit diseased state. Both lung-on-a-chip models will be used to assess toxicity and efficacy of various vectors.