Novel blood-brain barrier permeable CDNF-derived therapeutic peptides for the protection and regeneration of dopamine neurons

Description du projet

Un nouveau traitement pour la maladie de Parkinson

De nouvelles données indiquent que le facteur neurotrophique de la dopamine cérébrale (CDNF), une chaîne polypeptidique contenant 161 acides aminés, peut inverser la neurodégénérescence in vitro et in vivo chez des modèles animaux de la maladie de Parkinson (MP). Les tests de ce facteur ont été couronnés de succès lors d’essais cliniques de phase I‑II sur des patients atteints de la MP. Cependant, du fait de la barrière hémato‑encéphalique, le CDNF doit être administré en grandeur réelle au cerveau des patients atteints de la MP par microchirurgie. Pour surmonter ce problème, le projet THERAPE, financé par l’UE, contribue au développement de courts peptides dérivés du CDNF en mesure de traverser la barrière hémato‑encéphalique et d’atteindre le cerveau. Ces peptides innovants sont très prometteurs pour le traitement de la MP car, grâce à une administration systémique, ils sont également susceptibles de traiter des symptômes non moteurs.

Objectif

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by the progressive loss of midbrain dopamine neurons that leads to the severe movement disorders and several non-motor symptoms. Available PD treatments do not provide long-lasting relief from the symptoms and do not slow down or stop the neurodegeneration.
Cerebral dopamine neurotrophic factor (CDNF) was shown to reverse the PD-associated neurodegeneration in vitro and in vivo in animal models. Currently, CDNF is tested in the phase I-II clinical trials in PD patients. Despite of the promising results, CDNF doesn’t pass through the blood brain barrier (BBB) and should be delivered to the brain of PD patients through the risky microsurgery. Thus, there is a great need for the CDNF variants that can penetrate through the BBB avoiding intracranial surgery. In addition, systemic delivery of BBB permeable CDNF would offer a possibility to treat non-motor symptoms.
Current proposal combines the cutting-edge molecular neurobiology and nanomedicine to develop the next generation CDNF-derived peptides that will be able to penetrate the BBB. For that 1) the length of CDNF will be reduced to enable penetration through the BBB, 2) CDNF fragment will be mutated to improve its stability in the blood and tissues and 3) CDNF fragment will be conjugated to nanoparticles to increase its stability and ability to penetrate the BBB. Our preliminary data showed the feasibility of this approach and holds great promises for the breakthrough in the treatment of PD. In addition, during the project applicant will be trained into independent group leader through the hands-on training in the top scientific laboratories and by managing the highly innovative research at the interface of different disciplines connecting three excellent scientists: Prof. Saarma, the world leading molecular neurobiology researcher, Prof. Laakkonen, the expert in homing peptides and Prof. Santos, the master of nanomedicine.