JUSTBRAIN
Blood-brain barrier junctions as targets for paracellular drug delivery to the brain
| Coordinatore |
Organization address
address: Hochschulstrasse 4 contact info |
| Nazionalità Coordinatore | Non specificata |
| Sito del progetto | http://www.justbrain-fp7.eu |
| Totale costo | 4˙062˙475 € |
| EC contributo | 2˙989˙845 € |
| Programma | FP7-HEALTH
Specific Programme "Cooperation": Health |
| Code Call | FP7-HEALTH-2009-singl |
| Anno di inizio | 2009 |
| Periodo (anno-mese-giorno) | 2009-11-01 - 2014-04-30 |
Partecipanti
| # | ||||
|---|---|---|---|---|
| 1 |
UNIVERSITAET BERN
Organization address
address: Hochschulstrasse 4 contact info |
CH (BERN) | coordinator | 641˙000.00 |
| 2 |
IFOM FONDAZIONE ISTITUTO FIRC DI ONCOLOGIA MOLECOLARE
Organization address
address: "Via Adamello, 16" contact info |
IT (MILAN) | participant | 617˙960.00 |
| 3 |
FORSCHUNGSVERBUND BERLIN E.V.
Organization address
address: Rudower Chaussee 17 contact info |
DE (BERLIN) | participant | 606˙925.00 |
| 4 |
KLINIKUM DER JOHANN WOLFGANG VON GOETHE UNIVERSITAET
Organization address
address: Theodor Stern Kai 7 contact info |
DE (FRANKFURT AM MAIN) | participant | 566˙600.00 |
| 5 |
INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE (INSERM)
Organization address
address: 101 Rue de Tolbiac contact info |
FR (PARIS) | participant | 381˙560.00 |
| 6 |
TP21 GMBH
Organization address
address: LUISENSTRASSE 14 contact info |
DE (BERLIN) | participant | 175˙800.00 |
| 7 |
F. HOFFMANN-LA ROCHE AG
Organization address
address: GRENZACHERSTRASSE 124 contact info |
CH (BASEL) | participant | 0.00 |
Mappa
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Obiettivo del progetto (Objective)
'To maintain homeostasis of the central nervous system (CNS) the blood-brain barrier (BBB) prevents the free transcellular passage of hydrophilic molecules from the blood into the CNS. Because of this, the BBB is now recognised as the major obstacle to the treatment of most neurological disorders, as it hinders the delivery of many potentially important therapeutic and diagnostic substances to the CNS. Previous approaches in improving drug delivery across the BBB, which have primarily aimed at highjacking the transcellular transport machinery that is dedicated to the selective transport of specific molecules across the BBB, have had limited success, especially with regard to large molecular weight drugs. Lack of knowledge on the molecular composition and function of cerebrovascular cell-to-cell junctions has hampered the development of safe strategies for paracellular drug delivery across the BBB until recently. Members of the JUSTBRAIN consortium have accumulated knowledge on the structure and function of BBB cell-to-cell junctions, identified endothelial signals controlling the expression of individual junctional proteins and have begun to develop approaches, which may either open or close BBB junctions. Using in vitro and in vivo BBB models and animal models of neurological disorders, where BBB opening may be therapeutic, JUSTBRAIN is dedicated to translate this basic knowledge into identifying an entire novel platform of drugable molecular targets that could be functionally modulated thus allowing to bypass the BBB via the paracellular route. By these means JUSTBRAIN expects to improve efficient delivery of large molecules into the CNS and thus to expand on diagnostic and therapeutic possibilities for neurological disorders.'
Introduzione (Teaser)
The treatment of various neurological diseases necessitates drug access to the brain. A European study gained fundamental knowledge on how to improve drug delivery to the brain.
Descrizione progetto (Article)
The blood-brain barrier (BBB) is a vascular network that forms a structural and chemical barrier between the brain and blood circulation. BBB protects the brain from harmful substances and maintains its homeostasis. However, it also hinders the delivery of therapeutic drugs to the central nervous system, making it impossible to treat many brain diseases and brain cancer.
So far, drug delivery attempts have used specific transmembrane proteins that are in place for the effective delivery of nutrients from the blood to the brain, and for the removal of toxic metabolites. Recent evidence indicates that the space between the BBB endothelial cells is sealed by tight junctions.
Scientists on the EU-funded 'Blood-brain barrier junctions as targets for paracellular drug delivery to the brain' (http://www.justbrain-fp7.eu/ (JUSTBRAIN)) project exploited this information to develop strategies for transiently opening the BBB junctions. The plan was to target the tight junction proteins and facilitate a controlled and safe delivery of drugs into the brain.
To find suitable targets, the consortium firstly characterised the molecular composition of BBB tight junctions in healthy and diseased brains. They used human samples and tissue from different mouse models of neurological disorders such as Alzheimer's disease, stroke and multiple sclerosis. Despite the complex molecular composition of BBB tight junctions, in most cases absence of one molecule did not impact junctional integrity.
Nonetheless, scientists found three genes (CCM1, -2 and -3) that were crucial for the maturation and maintenance of endothelial cells in the brain. In addition, they identified an implication of the Wnt signalling pathway in brain vasculature, and manipulation of the pathway translated into the opening of the BBB tight junctions.
This pharmacological targeting of the Wnt signalling pathway was proposed as a potential strategy for transiently increasing the permeability of the BBB. Implementation of this approach should open up new avenues for the therapy of neurological diseases.