Nucleic Acid–Based Therapeutics for Parkinson’s Disease

  • Masayuki Nakamori
  • Eunsung Junn
  • Hideki Mochizuki
  • M. Maral MouradianEmail author


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.


α-Synuclein Antisense oligonucleotides MicroRNA Gene therapy Neurodegeneration 



This work was supported by AMED under Grant Number JP17ek0109195. E.J. is supported by the NIH (NS070898 and NS095003) and the State of New Jersey. M.M.M. is the William Dow Lovett Professor of Neurology and is supported by the Michael J. Fox Foundation for Parkinson’s Research, the American Parkinson Disease Association, and the New Jersey Health Foundation/Nicholson Foundation, and by grants from the US National Institutes of Health (AT006868, NS073994, NS096032, and NS101134).

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M.N. and H.M. have a pending patent (WO2017119463A1) relevant to this work. E.J. and M.M.M. hold patents on RNA targeting in alpha-synucleinopathies.

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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  1. 1.Department of NeurologyOsaka University Graduate School of MedicineSuitaJapan
  2. 2.Robert Wood Johnson Medical School Institute for Neurological Therapeutics, and Department of Neurology, Rutgers Biomedical and Health SciencesPiscatawayUSA

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