Recent developments in gene therapy for Parkinson's disease

Abstract

Parkinson's disease (PD) is a progressive, neurodegenerative disorder for which there is currently no cure. Gene therapy has emerged as a novel approach offering renewed hope for the development of treatments that meaningfully alter the course of the disease. In this review, we explore various gene therapy strategies currently being developed targeting key aspects of PD pathogenesis: the restoration of the dopamine system by delivering genes involved in dopamine biosynthesis, reinforcing the inhibitory signaling pathways through glutamic acid decarboxylase (GAD) delivery to increase GABA production, enhancing neuronal survival and development by introducing various neurotrophic factors, delivery of genes to complement recessive familial PD mutations to correct mitochondrial dysfunction, restoring lysosomal function through delivery of GBA1 to increase glucocerebrosidase (GCase) activity, and reducing α-synuclein levels by reducing or silencing SNCA expression. Despite promising early work, challenges remain in developing safe, effective, and long-lasting gene therapies. Key considerations include optimizing viral vectors for targeted delivery, achieving controlled and sustained gene expression using different promoters, minimizing immune responses, and increasing transgene delivery capacity. Future prospects may involve combinatory strategies targeting multiple pathways, such as multi-gene constructs delivered via high-capacity viral systems.

Keywords: AAV; HSV-1; Parkinson’s disease; dopamine neurons; gene therapy; growth factor delivery; lentivirus; neuromodulation.