Gene therapy targeting mitochondrial pathway in Parkinson’s disease

Chi-Jing Choong, Hideki Mochizuki

Parkinson's disease (PD) presents a relative selective localization of pathology to substantia nigra and well-defined motor symptoms caused by dopaminergic degeneration that makes it an ideal target for gene therapy. Parallel progress in viral vector systems enables the delivery of therapeutic genes directly into brain with reasonable safety along with sustained transgene expression. To date, gene therapy for PD that has reached clinical trial evaluation is mainly based on symptomatic approach that involves enzyme replacement strategy and restorative approach that depends on the addition of neurotrophic factors. Mitochondrial dysregulation, such as reduced complex I activity, increased mitochondria-derived reactive oxygen species (ROS) production, ROS-mediated mitochondrial DNA damage, bioenergetic failure, and perturbation of mitochondrial dynamics and mitophagy, has long been implicated in the pathogenesis of PD. Many of mutated genes linked to familial forms of PD affect these mitochondrial features. In this review, we discuss the recent progress that has been made in preclinical development of gene therapy targeting the mitochondrial pathway as disease modifying approach for PD. This review focuses on the potential therapeutic efficacy of candidate genes, including Parkin, PINK1, alpha synuclein, PGC-1 alpha, and anti-apoptotic molecules.