Nucleic Acid–Based Therapeutics for Parkinson's Disease

Abstract

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.

Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys

“…While clinical interventions with oligonucleotide therapeutics (ASO, siRNA, miRNA) have a long way to go, numerous recent advances in modified oligonucleotide technology and improvements in delivery systems highlight RNA therapeutics as a cutting-edge treatment for neurodegenerative diseases. 22 , 66 , 67 , 68 , 69 In this regard, several reports suggest that partial suppression of target gene expression is well tolerated in nonhuman primates and further supports oligonucleotides as potential therapy for amyotrophic lateral sclerosis or Huntington's diseases. 69 , 83 …”

“…Preclinical studies in rodents and nonhuman primates have successfully shown that α-syn can be down-regulated in PD-affected brain areas after direct application of oligonucleotide therapeutics including antisense oligonucleotides (ASO), small interfering RNAs (siRNA) and microRNAs (miRNA). 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 However, one potential caveat is that in some of the animal model paradigms, a marked α-syn downregulation induced by viral vector-mediated delivery of short hairpin RNA (shRNA) displayed toxicity in nigral dopamine (DA) neurons, thus opposing the potential therapeutic effect. 24 , 25 , 26 , 27 Irrespectively of these potential hitches, a rate-limiting step in the development of oligonucleotide-based therapeutics is the delivery to the brain compartment, and once there, to selected neuronal populations across the lipid bilayer of the cell and endosomal membranes.…”

MicroRNA-18a-5p Administration Suppresses Retinal Neovascularization by Targeting FGF1 and HIF1A

“…Dozens of miRNAs have been used as diagnostic and prognostic biomarkers, and some miRNAs intended to treat diseases as varied as cancer, hepatitis, and scleroderma have reached clinical trials (Maurer et al, 2010;Bader, 2012;Janssen et al, 2013). It is easier to design and synthesize oligonucleotide-based drugs than to identify small molecules, and it makes the process of identifying active ncRNA drugs much faster than that of small-molecule drugs (Matsui and Corey, 2017;Nakamori et al, 2019). To utilize the mammalian RNAi pathway for potent and specific inhibition of putative therapeutic targets, RNAi drugs have the same advantages (Setten et al, 2019).…”

MicroRNAs Dysregulation and Metabolism in Multiple System Atrophy

“…However, an additional challenge exists for miRNA mimics in the treatment of neurodegenerative diseases due to the blood–brain barrier. Virus vector-mediated delivery and specifically designed polymeric nanoparticles may be useful; however, further studies are needed (Saraiva et al, 2016; Nakamori et al, 2019).…”