Parkinson's disease (PD) is a progressive
neurodegenerative disorder that is diagnosed largely on clinical grounds due to characteristic motor manifestations that result from the loss of nigrostriatal dopaminergic neurons. While traditional pharmacological approaches to enhance
dopamine levels, such as with
L-dopa, can be very effective initially, the chronic use of this
dopamine precursor is commonly plagued with motor response complications. Additionally, with advancing disease, non-motor manifestations emerge, including
psychosis and
dementia that compound patient disability. The pathology includes hallmark intraneuronal inclusions known as Lewy bodies and Lewy neurites that contain fibrillar α-
synuclein aggregates. Evidence has also accumulated that these aggregates can propagate across synaptically connected brain regions, a phenomenon that can explain the progressive nature of the disease and the emergence of additional symptoms over time. The level of α-
synuclein is believed to play a critical role in its fibrillization and aggregation. Accordingly,
nucleic acid-based
therapeutics for PD include strategies to deliver
dopamine biosynthetic
enzymes to boost
dopamine production or modulate the basal ganglia circuitry in order to improve motor symptoms. Delivery of trophic factors that might enhance the survival of dopamine neurons is another strategy that has been attempted. These gene therapy approaches utilize viral vectors and are delivered stereotaxically in the brain. Alternative disease-modifying strategies focus on downregulating the expression of the α-
synuclein gene using various techniques, including modified
antisense oligonucleotides,
short hairpin RNA,
short interfering RNA, and
microRNA. The latter approaches also have implications for
dementia with Lewy bodies. Other PD genes can also be targeted using
nucleic acids. In this review, we detail these various strategies that are still experimental, and discuss the challenges and opportunities of
nucleic acid-based
therapeutics for PD.