Polymeric nanoparticle-mediated GBA1 gene therapy is neuroprotective in a preclinical model of Parkinson's disease.

Parkinson’s disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN). It manifests with hallmark motor symptoms such as tremors, rigidity, and bradykinesia, as well as severe non-motor complications. Current therapies provide symptomatic relief but fail to halt or reverse neurodegeneration, emphasizing that a disease-modifying treatment option is sorely needed. Mutations in glucocerebrosidase 1 (GBA1) gene encoding GCase or mutation-free reduction of GCase activity disrupt lysosomal function and drive α-synuclein (α-syn) accumulation, thereby leading to neuronal and motor function loss. To this end, restoring GCase activity by GBA1 gene therapy would potentially benefit a broad PD population with or without the genetic risk by intervening with the natural trajectory of the disease. In this study, we implemented localized GBA1 gene therapy by intracranial convection-enhanced delivery of plasmid DNA comprising human GBA1 gene carried by engineered polymeric nanoparticles capable of mediating widespread neuronal transgene expression. In an α-syn preformed fibril (PFF)-induced mouse model of PD, our therapeutic strategy mediated robust human GBA1 transgene expression in the SN to significantly reduce α-syn aggregation/accumulation, preserve tyrosine hydroxylase-positive dopaminergic neurons, and mitigate neuroinflammation. Remarkably, motor deficits were markedly improved, as demonstrated by grip strength, pole, and open field tests. These findings underscore the transformative potential of our nanoparticle-based GBA1 gene therapy in addressing the limitations of current standard-of-care treatments. We expect that our therapeutic strategy, upon clinical development and translation, may contribute to shifting the therapeutic paradigm from the current symptomatic management toward disease modification to ultimately provide PD patients with a curative therapeutic option.