Engineering the immune response in Parkinson’s disease to curb its pathological progression

Mounting evidence has defined the key role played by the immune system in exacerbating dopaminergic neuron loss in Parkinson’s disease (PD). Pathological alpha-Synuclein (αSYN) activates microglia and recruits inflamed T cells, creating a toxic environment that directly negatively impact on neurodegenerative processes. Blocking or attenuating neuroinflammation can have a strong therapeutic potential in PD, but systemic treatments are associated with immune system general suppression leading to severe and unacceptable side effects. Therefore, a therapeutic strategy for long-term and local immune suppression would minimize adverse effects and provide a long-sought disease-modifying treatment for PD. To achieve this goal, we have generated αSYN-specific CAR T regulatory cells (Tregs) that are activated and recruited only in the presence of toxic αSYN aggregates, suppressing immune activation. Herein, we will determine the therapeutic efficacy of mouse and human αSYN-CAR Tregs in conventional and humanized mice with virally-induced synucleinopathy. These experiments will determine the dose and infusion schedule that will achieve maximal neuroprotection and symptomatic rescue with none or minimal side effects. Moreover, innovative all-human neuroimmune organoids will be generated by assembling patient and isogenic iPSC-derived neural, astroglial and microglial cells together with freshly isolated T cells and αSYN-CAR Tregs. This model will recapitulate human-specific neuroinflammatory processes and validate the capacity of αSYN-CAR Tregs to interfere with them. Finally, we conceived αSYN-CAR Tregs as ideal cellular shuttles for the local delivery of therapeutic molecules and this concept will be explore to express αSYN anti-aggregating agents. This treatment is of potential benefit for the entire PD patient population at any given stage of the disease and pharmacological regimen, and with a straightforward clinical implementation path using an autologous cellular source.