Targeting α-Synuclein Aggregation in Parkinson's Disease: A Narrative Review of Current Gene Therapy Strategies

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the accumulation of misfolded α-synuclein (α-syn) aggregates, leading to dopaminergic neuronal loss and motor dysfunction. Current pharmacological treatments primarily provide symptomatic relief and have a limited impact on disease progression. This article presents a narrative review of emerging gene therapy approaches aimed at modulating α-syn expression, aggregation, and clearance as potential disease-modifying strategies for PD. Gene-based interventions include viral vector-mediated gene delivery, antisense oligonucleotides, RNA interference, and gene-editing technologies. Preclinical studies and early-phase clinical trials suggest that these approaches may reduce α-syn burden, improve motor outcomes, and support dopaminergic neuron preservation. Adeno-associated viral and lentiviral vectors have demonstrated promise for targeted central nervous system delivery, although challenges related to dosage optimization, regional specificity, long-term safety, and immune responses remain. Complementary strategies focusing on enhancing molecular chaperone activity and activating autophagy-lysosomal pathways have also shown potential in facilitating α-syn clearance. Despite encouraging progress, several limitations hinder clinical translation, including off-target effects, immune activation, and the need to preserve physiological α-syn functions essential for neuronal homeostasis. Future success will depend on precise molecular targeting, optimized delivery platforms, and rigorous safety evaluation through well-designed clinical trials. This narrative review summarizes current advances, key limitations, and future directions in α-syn-targeted gene therapy, highlighting its potential role in advancing PD treatment beyond symptomatic management toward disease modification.