Gene therapy for Parkinson's disease: current landscape, translational challenges, and future directions

Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by dopaminergic neuronal loss. Gene therapy has emerged as a disease-modifying strategy capable of targeting these mechanisms through dopamine restoration, neurotrophic support, and correction or silencing of pathogenic mutations, which collectively contribute to neuronal vulnerability and α-Synuclein-driven degeneration.

Herein, the authors synthesize contemporary viral and non‑viral platforms designed to restore dopamine biosynthesis, deliver neurotrophic factors, and correct pathogenic mutations (GBA1, LRRK2, PINK1). The authors summarize clinical translation with emphasis on trials targeting dopamine synthesis (AAV2 AADC, ProSavin/AXO Lenti PD), neurotrophic factors (AAV2 GDNF, AAV2 NRTN), pathogenic variants (AAV9 GBA1/PR001; LRRK2 RNAi; emerging CRISPR/PINK1 strategies), and circuit modulation (AAV GAD), correlating mechanistic ration. They also examine translational challenges including vector biodistribution and immune responses.

Gene therapy for PD is transitioning from symptomatic modulation toward targeted molecular correction. Clinical trials have validated durable, neuron-specific expression using AAV and lentiviral vectors and demonstrated target engagement across dopamine synthesis, trophic support, and genetic mutation-specific strategies. Persistent challenges include limited vector biodistribution, reduced retrograde transport in advanced disease, immune variability, and surgical infrastructure requirements. Overcoming these via engineered capsids, delivery optimization, and validated biomarkers will enable precision, stage‑specific interventions.