A Review of Genetic and Gene Therapy for Parkinson's Disease

Abstract

Parkinson's disease (PD) is a syndrome with deterioration of neurons, with its onset starting in the '20s, known as the young beginning of Parkinson's to the late inception of the ailment in the 60s. The majority of the environmental risk associated with PD is age. The pathophysiology of PD is related to the accretion of synuclein alpha (SNCA) protein leading to toxicity. This toxicity further leads to a depletion in dopamine levels, creating both motor and non-motor symptoms. PD is the combination of genetic and environmental risk factors. Linkage and association studies provided data on autosomal dominant and recessive genes linked to PD. Current treatment regimes involve using levodopa, catechol-O-methyl transferase inhibitors, anticholinergics, and monoamine oxidase B (MAO-B) inhibitors. Genetic treatment is done by identifying possible targets. Gene therapy includes silencing, replacing, or correcting the flawed gene with a good gene. This therapy has the advantage of eliminating significant PD symptoms with fewer to no adverse effects than conventional treatment. These targets are organized into disease-modifying or non-disease modifying. The distinction between these two is that disease-modifying treatment stops the degeneration of neurons, while non-disease modifying treatment involves dopaminergic enzyme expression. In non-modifying targets, aromatic L-amino acid decarboxylase (AADC) therapy is used but not as a standalone, so the presentation of AADC, tyrosine hydroxylase (TH), and GTP cyclohydrolase 1 (GCH) is done together as a tricistronic system. With these developments, a drug named prosavin is under clinical phase 1 trial. Disease-modifying targets involve glial cell-derived neurotrophic factor (GDNF). Direct GDNF delivery reduces PD symptoms. This GDNF infusion technique works with a tetracycline-controlled transactivator. Gene therapy introduction into the treatment of PD would be beneficial as there would be lesser adverse effects seen as linked with conventional treatment involving levodopa, MAO-B inhibitors, and anticholinergics, among a few. This article discusses the genetic basis and genetic model of therapy for PD.

Keywords: gene therapy; levodopa; motor symptoms; parkinson’s disease; snca protein.

Figure 1. PRIMSA 2020 flow diagram for the systematic review

PRIMSA: Preferred Reporting Items for Systematic and Meta-analysis, PMC: PubMed Central.

Figure 2. Pathophysiology of PD with the expression of proteins from various genes.