Preclinical evaluation of nitrated α-synuclein-specific CAR-Treg therapy in Parkinson's disease

Current evidence indicates that Parkinson's disease (PD) involves T cell-mediated inflammation, which plays a fundamental role in promoting neuroinflammation and neurodegeneration in patients and animal models. These T cells are specific to α-synuclein-derived antigens, including nitrated α-synuclein (NαSyn). Here, we sought to develop an experimental immunotherapy for PD based on the generation of regulatory T cells (Treg) specific to NαSyn, using the chimeric antigen receptor (CAR) technology. Accordingly, we first obtained an antibody specific to human α-synuclein containing three nitrated tyrosine residues (3NY-hαSyn), which displayed specific immunoreactivity in the serum of PD patients which correlated with the clinical score. Afterward, we generated CAR-Treg specific to 3NY-hαSyn and tested them in two PD models involving human α-synuclein. The CAR-Treg therapy substantially inhibited the inflammatory T cell response specific to α-synuclein-derived antigens, neuroinflammation, neurodegeneration, and the motor decline. This preclinical study indicates that the CAR-Treg therapy represents a promising therapeutic strategy for treating PD patients.