Investigational Gene Therapies for Parkinson's Disease

Abstract

Since the publication of the first gene therapy clinical trial in Parkinson's disease (PD) in 2007, rapid advances have resulted in escalating interest in applying this technology to manipulate various cellular processes altered in PD. There is now a rich literature describing the various approaches taken, including modulating aberrant networks, restoring dopamine, and mitigating deleterious effects of known gene mutations or as a restorative therapy. Evidence has accrued supporting feasibility, safety, and tolerability of initial gene therapy approaches, as well as providing initial indications of efficacy in several cases. However, there have also been unexpected challenges, and technology is still evolving, making this an important time point to evaluate what has been learned and to place it in context to support ongoing and future efforts. In this review, we focus on the potential of gene therapy to ameliorate symptoms and modify disease progression in PD. We critically review previous clinical research, we address potential benefits and predicted limitations, and we address pipeline approaches aiming to bring a gene therapy approach to the clinic.

Fig. 1

Currently tested approaches for gene and gene modulation therapies in Parkinson’s disease. The figure depicts a combination of approaches in completed, ongoing, or planned phase 1 or 2 trials. On the left of the figure delivery methods comprise direct neurosurgical infusion, intrathecal delivery of small molecules (SM) and antisense oligonucleotides (ASO), as well as possible novel delivery systems such as opening the blood–brain barrier (BBB) at specific target locations by use of MRI-guided focused ultrasound (MRgFUS). The right of the figure depicts the intended mechanism of action of gene and enzymatic modulation interventions: biological interventions (purple); enzymatic modulation strategies (light blue); as well as structures that include the neuronal cell membrane (brown) and cell nucleus (black). Dashed blue lines separate macroanatomy (basal ganglia on the left), from microanatomy (e.g cellular biology on the right). GDNF glial-derived neurotrophic factor, NRTN neurturin, RET rearranged during transfection receptor, Nurr1 nuclear receptor related 1 protein, AAV2 adeno-associated virus type 2, AADC aromatic l-amino decarboxylase, GAD glutamic acid decarboxylase, GABA gamma amino butyric acid, A-Syn phosphorylated alpha-synuclein, GBA1 glucocerebrosidase 1 gene, GCase glucocerebrosidase enzyme, DOPA dihydroxy-l-phenylalanine