Projektbeschreibung
Verabreichung von Therapeutika an das Gehirn: Entwicklung eines neuen Hirntransporters
Die Blut-Hirn-Schranke (BHS) erschwert die Verabreichung von Therapeutika an das Gehirn, wodurch die Behandlungsmöglichkeiten für Krankheiten wie Krebs und neurodegenerative Erkrankungen eingeschränkt wird. Die derzeitigen Methoden zur Verabreichung von Arzneimitteln über die BHS leiden unter der begrenzten Transporteffizienz und der peripheren Gewebeaufnahme, wodurch der therapeutische Index von Arzneimitteln, die für das Gehirn bestimmt sind, gesenkt wird. Im Rahmen des vom Europäischen Forschungsrat finanzierten Projekts OBGate wird vorgeschlagen, einen neuen orthogonalen Rezeptor zu entwickeln, der Medikamente wirksam durch die Blut-Hirn-Schranke transportieren kann und nur im Hirnendothel exprimiert wird. Die Forschenden werden einen neuen BHS-Transporter entwerfen und ihn mithilfe eines Nanoträgers verabreichen, der die Art und Weise nachahmt, wie Viren in Zellen eindringen. Dieser Ansatz birgt das Potenzial, den Hirntransport zu revolutionieren und die Behandlungsmöglichkeiten für neurologische Erkrankungen zu verbessern.
Ziel
Many impairing illnesses raging from metastatic cancers to neurodegenerative diseases affect the brain. Unfortunately, delivery of therapeutics to the brain is highly challenging due to the blood-brain barrier (BBB). Despite decades of research, no safe and efficient strategy to overcome this barrier has reached clinical application. Here we propose a concept that will revolutionize brain transport: creating a new orthogonal receptor to mediate transport across the BBB. Numerous molecules have been developed to achieve brain delivery via receptor-mediated transport. However, delivery is very limited presumably because no receptor combines 3 key features: high transport efficiency, high expression on the BBB, and low expression on peripheral tissues. This results into peripheral tissues acting as a sink and dramatically lowering the therapeutic index of drugs aimed for the brain. The greatest limitation of current efforts is trying to solve both selectivity and efficient transport in a single delivery vehicle. Our unprecedented approach is based on dissecting this problem in two: increasing transport efficiency with the new orthogonal receptor OBGate and addressing selectivity with a highly efficient targeted vehicle to express the receptor only at the BBB. Since this receptor will not bind any endogenous ligand, its properties and intercellular trafficking can be engineered with minimal alteration of brain homeostasis. This will enable to unravel the key determinants of BBB transport and to build an ideal transport system. Selective expression of this receptor in the brain endothelium will be achieved by engineering a gene delivery nanocarrier mimicking the two-stage viral entry into BBB cells. As an example to prove the efficiency of our system we will aim to deliver biotherapeutics for the treatment of brain metastatic breast cancer. Overall, we will open a new gate to the brain that is poised to be paradigm-breaking in the treatment of neurological diseases.
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
ERC - Support for frontier research (ERC)Gastgebende Einrichtung
08017 Barcelona
Spanien