Gene Correction Enhances Dopaminergic Cell Therapy in a Nonhuman Primate Model of Parkinson's Disease

ABSTRACT Human induced pluripotent stem cell (iPSC)‐derived dopaminergic progenitors offer a promising strategy for cell replacement in Parkinson's disease (PD), yet their long‐term efficacy and safety in primates remain underexplored. Here, we generated isogenic iPSC lines from a PD patient carrying compound LRRK2 mutations (R50H and M2397T) and used CRISPR/Cas9 and prime editing to correct these variants. Both mutant and gene‐corrected lines were differentiated into midbrain dopaminergic progenitors (DA‐NPCs), characterized in vitro, and transplanted bilaterally into the striatum of MPTP‐lesioned cynomolgus monkeys. Over 18 months, grafted cells survived, expressed TH and GIRK2, and exhibited mature electrophysiological properties. [ 1 8 F] DOPA PET imaging revealed restored dopamine synthesis in both grafting groups, with no statistically significant differences observed between mutant and gene‐corrected groups. Behavioral assessments showed sustained motor improvements and enhanced exploratory behavior. No tumor formation or adverse astrocytic response was observed, and systemic safety markers remained normal. These findings demonstrate that both mutant and corrected DA‐NPCs integrate and function in the primate brain. Our results support the feasibility of personalized regenerative therapies for genetic PD.