Work packages

General structure and main deliverables

These are task-based services that are necessary to reach our results. Each work package (WP) comes with it’s own deliverables.

WP1 - Identification of genes or pathways candidates associated with neurodegenerative diseases and expressed in brain endothelial cells

  • Genetic analyses of existing data (GWAS, others)
  • Transcriptomic, proteomic on patient primary cells or tissues
  • Transcriptomic, proteomic on preclinical disease models primary cells
  • Glycomics of BBB cells and/or cerebral vasculature of diseased brains
Deliverables: Candidates disease-associated or differentially expressed genes or pathways in brain endothelial cells

WP2 - Phenotypic validation of these genes or pathways in endothelial cells

  • Generation of endothelial cells from iPSC or Progenitors
  • Generation of iPSC cells from primary cells from patients
  • Induce mutations of genes/pathways involving BBB permeability and transport by genome editing (such as CRISPR cas9 technology)
  • Produce evidence for phenotypic or transport differences in monocultures or 3D/co-cultures
Deliverables: Validated disease-specific or differentially expressed genes or pathways of potential relevance to brain transport

WP3 - Develop best state-of-the-art (e.g. hiPSC- or progenitor-derived) BBB models

  • Differentiation into brain endothelial cells and barrier formation characterization
  • Mono- or co-cultures, 3D-settings, microfluidics or other settings
  • Mathematical/in silico modelling of receptor-/carrier-mediated transcytosis across the BBB and PK of biopharmaceutics in the brain
Deliverables: At least one in vitro BBB-model and an in silico model reproducing/predicting disease features and BBB permeability in vivo in healthy and disease state. Characterize apical/basolateral receptor activity, validate model by comparing to in vivo BBB properties, validate candidates in vitro

WP4 - Characterisation of neurotropic virus-based BBB and brain penetration mechanisms

  • Genetic and proteomics analyses of the viral genes, proteins and protein fragments for their interactions with human cells and proteins
  • Cellular, molecular and biochemical characterization of viral interactions with cellular proteins and/or receptors and virus-mediated penetration of BBB or peripheral nerve/neuronal cells;
  • Preparation and testing of viral particles (empty viral vesicles) for interactions and penetration across the BBB in vitro or in vivo animal models;
Deliverables: new targets/mechanisms and/or delivery systems for selective BBB delivery

WP5 - Follow-up on identification and characterisation of new potential targets from WP2

  • New mechanisms of brain delivery; including synergy with potential new mechanisms identified in COMPACT.
  • New potential targets involved in the vascular hypotheses of neurodegeneration.
Deliverables: Tools for validation of the new mechanisms (Ab’s, ligands, cell lines). Validated new brain-delivery targets (by demonstration of increased in vivo brain exposure of Ab or ligand of the target). Validated new neurovascular target with potential in a neurodegenerative disease in disease model.

WP6 - Management, communication, dissemination

  • Overall coordination of the scientific work packages, budgets, delivery and dissemination of findings and sustainability planning.
Deliverables: Tools for data exchange, reports, publications

Proposed structure

Proposed structure

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