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Name IM2PACT
Long Name Investigating mechanisms and models predictive of accessibility of therapeutics into the brain
Description Investigating mechanisms and models predictive of accessibility of therapeutics into the brain. As the name suggests, the blood-brain barrier (BBB) tightly controls access to our brains, allowing nutrients and essential substances through, but blocking pathogens, for example. Getting medicines through this protective shield is a major challenge for drug developers, particularly those developing biopharmaceuticals, which are based on large molecules like proteins and antibodies. The goal of IM2PACT is to advance our understanding of the BBB to facilitate the development of more effective treatments for a range of neurological and metabolic disorders. Specifically, the project aims to develop better models of the BBB so that researchers can study it more easily; investigate the biology of the BBB in both health and disease, and the transport routes across it; and to develop innovative systems capable of delivering medicines to the brain. The project will focus on two major disease areas: neurodegenerative diseases, including Alzheimer and Parkinson’s diseases, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease and motor neurone disease), vascular dementia, and multiple sclerosis; and metabolism-related diseases (mainly diabetes and obesity).
Objectives 1. Identify and validate specific genes and/or mechanisms which are altered in brain endothelial cells in disease. 2. Generate, validate and characterised robust and predictive iPSC-derived BBB models. 3. Expand and deepen the understanding of the fundamental processes that underpin drug-trafficking across the BBB. 4. Characterise new genetic models for the diseases of interest in this topic which are better amenable to evaluate disease-modifying agents. 5. Characterised mechanisms of neurotropic virus-mediated BBB and CNS penetration for development of selective brain delivery systems. 6. Established in silico/mathematical models in predicting BBB penetration of therapeutics (such as receptor-or carrier-mediated transcytosis for delivery across the BBB) and pharmacokinetics of biopharmaceutics in different compartments of CNS. 7. Identify relevant translational readouts which are better amenable to elucidate the role of the BBB in the pathogenesis of neurodegeneration and could eventually lead to new targets for the treatment of the neurovascular causes of the diseases.
Website http://im2pact.org/
Start date 01-01-2019
End date 31-12-2023
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Name Projects Type of institution Country  
Janssen Pharmaceutica NV EPAD ADAPTED AMYPAD IMPRiND EQIPD NEURONET EMIF IM2PACT PHAGO PRISM RADAR-CNS RADAR-AD ROADMAP IDEA-FAST Pharma-Cog EPND EFPIA Belgium
Sanofi-Aventis Recherche & Developpement EPAD EQIPD AETIONOMY IM2PACT PHAGO NEURONET Mobilise-D IDEA-FAST EPND EFPIA France
H. Lundbeck As EPAD IMPRiND IM2PACT PD-MitoQUANT PHAGO RADAR-CNS ROADMAP Pharma-Cog EFPIA Denmark
Novartis Pharma AG EPAD IMPRiND EQIPD AETIONOMY IM2PACT PRISM RADAR-AD ROADMAP Mobilise-D Pharma-Cog EPND EFPIA Switzerland
Pfizer Limited EPAD EQIPD EMIF IM2PACT PRISM Mobilise-D IDEA-FAST EFPIA United Kingdom
Cardiff University EPAD IM2PACT Academia United Kingdom
VU University Medical Center Amsterdam EPAD AMYPAD IM2PACT PRISM MOPEAD RADAR-CNS RADAR-AD EMIF PRISM2 Pharma-Cog EPND Academia Netherlands
University Of Oxford EPAD IMPRiND IM2PACT RADAR-AD ROADMAP EMIF EPND Academia United Kingdom
Academisch Ziekenhuis Leiden PRISM IM2PACT ROADMAP IDEA-FAST PRISM2 Academia Netherlands
Aarhus Universitet IMPRiND IM2PACT ROADMAP EMIF Academia Denmark
University Of Dundee IMPRiND IM2PACT Academia United Kingdom
Novo Nordisk AS IM2PACT EMIF EFPIA Denmark
Universitaetsmedizin Der Johannes Gutenberg-Universitaet Mainz EQIPD IM2PACT Academia Germany
Mimetas BV ADAPTED IM2PACT PD-MitoQUANT SME Netherlands
Fujifilm Cellular Dynamics Inc IM2PACT EFPIA United States
Ait Austrian Institute Of Technology Gmbh IM2PACT Academia Austria
Kobenhavns Universitet IM2PACT ROADMAP EMIF Academia Denmark
Ruprecht-Karls-Universitaet Heidelberg IM2PACT Academia Germany
Stiftung Tieraerztliche Hochschule Hannover IM2PACT Academia Germany
The Open University IM2PACT Academia United Kingdom
The University Of Sheffield IM2PACT Mobilise-D Academia United Kingdom
Universita Degli Studi Di Modena e Reggio Emilia IM2PACT Academia Italy
Universitaetsklinikum Wuerzburg - Klinikum Der Bayerischen Julius-Maximilians-Universitat IM2PACT Academia Germany
Uppsala Universitet IM2PACT Academia Sweden
Artemis One Health Research BV IM2PACT SME Netherlands
Neuway Pharma Gmbh IM2PACT SME Germany
Pharmacoidea Fejleszto Es Szolgaltato Kft IM2PACT AETIONOMY SME Hungary
WP number Description Project  
WP1 Identification of genes or pathways candidates associated with neurodegenerative diseases and expressed in brain endothelial cells IM2PACT
WP2 Phenotypic validation of genes or pathways in endothelial cells IM2PACT
WP3 Develop best state-of-the-art (e.g. hiPSC- or progenitor-derived) BBB models IM2PACT
WP4 Characterisation of neurotropic virus-based BBB and brain penetration mechanisms IM2PACT
WP5 Follow-up on identification and characterisation of new potential targets from WP2 IM2PACT
WP6 Management, communication, dissemination IM2PACT
Deliverable number Title Project Submission date Link Keywords  
No entries in table
Title First author last name Year Project Link Keywords  
Transport Studies Using Blood-Brain Barrier In Vitro Models: A Critical Review and Guidelines Santa-Maria 2020 IM2PACT https://doi.org/10.1007/164_2020_394 Book Chapter, Brain capillary, endothelial cells, Cell layer tightness, Drug transport, Paracellular transport, Penetration, TEER
Brain endothelial LRP1 maintains blood–brain barrier integrity Storck 2021 IM2PACT https://doi.org/10.1186/s12987-021-00260-5 Blood–brain barrier integrity, Low-density lipoprotein receptor-related protein 1 (LRP1), P-glycoprotein/Abcb1 (P-gp), Tight junctions, Matrix metalloproteinases (MMPs), Cyclophillin A
A Microfluidic Multisize Spheroid Array for Multiparametric Screening of Anticancer Drugs and Blood-Brain Barrier Transport Properties Eilenberger 2021 IM2PACT https://doi.org/10.1002/advs.202004856 anticancer drugs; blood-brain barrier; in vitro tests; microfluidics; multicellular spheroids.
Neuropharmacokinetic visualization of regional and subregional unbound antipsychotic drug transport across the blood–brain barrier Luptáková 2021 IM2PACT https://doi.org/10.1038/s41380-021-01267-y brain, drug, concentrations, tissue, bbb, cortex, plasma, drugs, risperidone
PLGA-PEG-ANG-2 Nanoparticles for Blood–Brain Barrier Crossing: Proof-of-Concept Study Hoyos-Ceballos 2020 IM2PACT https://doi.org/10.3390/pharmaceutics12010072 PLGA; PEG; PF127; angiopep-2; nanoparticles; blood–brain barrier
Transendothelial Electrical Resistance Measurement across the Blood–Brain Barrier: A Critical Review of Methods Vigh 2021 IM2PACT https://doi.org/10.3390/mi12060685 blood–brain barrier; cell culture insert; electrodes; endothelial cell; epithelial cell; impedance; lab-on-a-chip; transendothelial electrical resistance; viscosity
Brain pharmacokinetics of two BBB penetrating bispecific antibodies of different size Faresjö 2021 IM2PACT https://doi.org/10.1186/s12987-021-00257-0 Bispecific antibody, Brain pharmacokinetics, Transferrin receptor, BBB
The Role of Sphingolipids and Specialized Pro-Resolving Mediators in Alzheimer’s Disease Wit 2021 IM2PACT https://doi.org/10.3389/fimmu.2020.620348 Alzheimer’s disease; bioactive lipids; ceramide; neuroinflammation; specialized pro-resolving mediator; sphingolipids; sphingosine-1-phosphate.
Hypoxia increases expression of selected blood-brain barrier transporters GLUT-1, P-gp, SLC7A5 and TFRC, while maintaining barrier integrity, in brain capillary endothelial monolayers Ozgür 2022 IM2PACT https://doi.org/10.1186/s12987-021-00297-6 Angiogenesis; Blood–brain barrier; Brain; Endothelial cells; Hypoxia; Low oxygen tension; Tight junctions.
Applications of the ROS-Responsive Thioketal Linker for the Production of Smart Nanomedicines Rinaldi 2022 IM2PACT https://doi.org/10.3390/polym14040687 ROS-responsive biomaterials; nanomedicine; nanoparticles; smart drug delivery systems; thioketal.
Tunneling Nanotubes: A New Target for Nanomedicine? Ottonelli 2022 IM2PACT https://doi.org/10.3390/ijms23042237 rug exchange; nanomedicine; nanoparticles; targeted therapy; therapeutic efficiency; tunneling nanotubes.
Microfluidic Technology for the Production of Hybrid Nanomedicines Ottonelli 2021 IM2PACT https://doi.org/10.3390/pharmaceutics13091495 nanomedicine; hybrid nanoparticles; nanoprecipitation; microfluidics
Tween® Preserves Enzyme Activity and Stability in PLGA Nanoparticles Duskey 2021 IM2PACT https://doi.org/10.3390/nano11112946 polymeric nanoparticles; enzyme delivery; enzyme stabilization; Tween® stabilization; nanomedicine
PCSK9 acts as a key regulator of Aβ clearance across the blood–brain barrier Mazura 2022 IM2PACT https://doi.org/10.1007/s00018-022-04237-x Alzheimer’s disease; Amyloid-beta; Blood–brain barrier; Low-density lipoprotein receptor-related protein 1; Monoclonal antibody therapy; Proprotein convertase subtilisin/kexin type 9.
Glioblastoma Multiforme Selective Nanomedicines for Improved Anti-Cancer Treatments Duskey 2022 IM2PACT https://doi.org/10.3390/pharmaceutics14071450 NMeds; brain tumour; cancer; drug delivery; drug targeting; glioblastoma; improved chemotherapeutics; nanomedicine; nanoparticles.
Title Description Type Project  
Omics data on patient tissue and cellular disease models

IM2PACT will identify genes or pathway candidates associated with neurodegenerative diseases and expressed in brain endothelial cells. To fulfil this aim IM2PACT will use genetic analyses of existing data (GWAS, others); transcriptomic, proteomic on patient primary cells or tissues; transcriptomic, proteomic on preclinical disease models primary cells and glycomics of BBB cells and/or cerebral vasculature of diseased brains. For more information please visit:

http://im2pact.org/contact/

dataset-non-clinical-im2pact-3 IM2PACT
In vitro and in silico models of the blood-brain barrier

IM2PACT will develop state-of-the-art in vitro blood-brain barrier (BBB) models by differentiating hiPSC into brain endothelial cells; it will also use mathematical modelling of receptor/carrier-mediated transcytosis across the BBB and pharmacokinetics of biopharmaceutics in the brain to create in silico BBB models reproducing/predicting disease features and BBB permeability in vivo, in both healthy and disease states. For more information, please visit:

http://im2pact.org/contact/

disease-model-non-clinical-im2pact-4 IM2PACT
On-chip microfluidic multisize spheroid array

Complex 3D biological systems such as multicellular spheroid and organoid technologies have been implemented to improve the predictability of preclinical in-vitro models. As an example of these systems, multicellular spheroid systems are able to mimic human (patho)physiologies, they are considered a promising alternative to bridge the gap between preclinical tests and in vivo outcomes by eliminating unsuitable agents early on, and can potentially lead to significantly lower pharmaceutical development costs by shortening development time, providing meaningful and representative test results.  This asset represents a microfluidic array to generate series of spheroids with different sizes and cellular compositions which can be used to investigate active and passive transport across the blood–brain barrier. In this way, these microfluidic multisize spheroid arrays close a critical technological gap.

https://onlinelibrary.wiley.com/doi/10.1002/advs.202004856

tools-non-clinical-im2pact-28 IM2PACT

 

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