Im2pact Consortium - 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

Work packages