Translational validation of neural organoid grafts for treating Parkinson’s and Huntington diseases – Parkington

The Parkington project aims at proposing a novel cell therapy approach for the treatment of neurodegenerative diseases, in particular for Parkinson’s and Huntington’s disease (PD and HD). In the past decade, pluripotent stem cells have provided unprecedented access to human cell types, with a special focus on human neurons. The possibility to generate patient specific isogenic cell lines or banks of immunomatched donor cell lines with the potential of covering almost the entire world population opens new perspectives for personalized cellular therapy. The neurons intended to replace dysfunctional or dying neurons originated until recently either from aborted fetuses or tumor cell lines derived from embryonic carcinoma. Neither source is amenable to large scale human neurodegenerative disease cellular therapy. The availability of human pluripotent stem cell lines combined with the development of very potent protocols to generate in vitro a variety of neuronal cell types was an important step to overcome the aforementioned ethical and logistical issues. However, besides the cell source, there is another limitation that makes human neuronal grafting not the strategy being pursued in clinical trials. Direct grafting of specific mature neurons is very inefficient due to their sensitivity to detachment and the fragility of the neuritic extensions, which leads to poor survival rate. An alternative cell therapy strategy consists in grafting neuronal precursors with the hope of proper maturation in situ. Although this method is still prevalently tempted, it is performed at the expense of the control of in situ neuronal identity and bears a risk of overgrowth. In the Parkington project, we propose that grafting neuronal organoids with size and cellular content control could circumvent this limitation. P#1’s team (E. Bezard) is a recognized expert in translational research on neurodegenerative diseases with an emphasis on PD. The interdisciplinary consortium built by P#1 is composed of 3 other complementary groups. P#2’s team (P. Nassoy) are physicists who have developed the Cellular Capsules Technology (CCT). CCT enables the encapsulation of human pluripotent stem cells in hollow hydrogel capsules and the production of neural tissues of controlled size. P#3’s team (A. Perrier) have developed protocols to generate both nigral dopaminergic neurons lost in PD and striatal GABAergic neurons lost in HD from human pluripotent stem cells. P#4’s team (A. Gaillard) have demonstrated that connectivity of grafted neural cells can recapitulate their physiological counterparts, especially in the context of nigro-striatal pathway reconstruction in PD. Preliminary data obtained through a local collaborative work between P#1 and P#2 have already paved the ground for this proposal. Validation of our approach up to a pre-clinical stage entails synergetic efforts between all partners to generate and characterize “Controlled Neuronal Organoids” (CNOs) and assess the behavioral outcomes of CNO grafting. We are confident that this project will demonstrate the potential of grafting CNOs in translational animal models of both PD and HD. This will foster the translation of this technology into preclinical studies and ultimately human cellular therapy. The Parkington project has the bold ambition to offer a much-needed alternative to drug-based symptomatologic treatments of both PD and HD.