Description du projet
Administration de médicaments thérapeutiques dans le cerveau: conception d’un nouveau transporteur cérébral
La barrière hémato-encéphalique (BHE) rend difficile l’administration des médicaments thérapeutiques dans le cerveau, ce qui limite les possibilités de traitement de maladies telles que le cancer et les maladies neurodégénératives. Les méthodes actuelles d’administration de médicaments à travers la BHE pâtissent d’une efficacité de transport et d’une absorption par les tissus périphériques limitées, ce qui réduit l’index thérapeutique des médicaments destinés au cerveau. Financé par le Conseil européen de la recherche, le projet OBGate propose de créer un nouveau récepteur orthogonal capable de transporter efficacement les médicaments à travers la BHE tout en étant exprimé uniquement dans l’endothélium du cerveau. Les chercheurs concevront un nouveau transporteur BHE et l’administreront au moyen d’un nanotransporteur qui imite la manière dont les virus pénètrent dans les cellules. Cette approche est susceptible de révolutionner le transport dans le cerveau et d’améliorer les options thérapeutiques pour les maladies neurologiques.
Objectif
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.
Champ scientifique
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thème(s)
Régime de financement
ERC - Support for frontier research (ERC)Institution d’accueil
08017 Barcelona
Espagne