Vania Broccoli (Italy), Alexander Dityatev (Germany) and Josè Luis Lanciego (Spain)

Degeneration of mesencephalic DA neurons triggers the initial phases of PD, which raises the concept that cell replacement might represent a long-term restorative option for this neuropathology. Indeed, previous studies in PD patients have indicated that cell therapy has the potential to significantly sustain an enduring symptomatic relief in at least some of them. However, an ideal renewable source of transplantable human DA neurons is lacking in many aspects. We have recently developed a methodology that promotes transdifferentiation of mouse and human fibroblasts into functional induced dopaminergic neurons (iDANs), which display sophisticated neuronal properties including pacemaking firing activity, synaptic integration, and activity-dependent dopamine release. Therefore, iDANs offer an unprecedented cellular source with ideal features for cell therapy in PD, since they can be generated from the patients in high amounts. Herein, we plan to push forward this technology by elaborating methods of direct in vivo reprogramming to induce in situ local neuronal transdifferentiation in relevant animal models of PD (mouse and monkey). Local delivery of the reprogramming factors will be optimized and the best cellular substrate identified in order to achieve the most efficient recovery of the neurological symptoms in the PD animal models.