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Antisense Oligonucleotides: Treating Neurodegeneration at the Level of RNA
Open accessAbstract
Adequate therapies are lacking for Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and other neurodegenerative diseases. The ability to use antisense oligonucleotides (ASOs) to target disease-associated genes by means of RNA may offer a potent approach for the treatment of these, and other, neurodegenerative disorders. In modifying the basic backbone chemistry, chemical groups, and target sequence, ASOs can act through numerous mechanisms to decrease or increase total protein levels, preferentially shift splicing patterns, and inhibit microRNAs, all at the level of the RNA molecule. Here, we discuss many of the more commonly used ASO chemistries, as well as the different mechanisms of action that can result from these specific chemical modifications. When applied to multiple neurodegenerative mouse models, ASOs that specifically target the detrimental transgenes have been shown to rescue disease associated phenotypes in vivo. These supporting mouse model data have moved the ASOs from the bench to the clinic, with two neuro-focused human clinical trials now underway and several more being proposed. Although still early in development, translating ASOs into human patients for neurodegeneration appears promising.
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“The most common injection route for nucleic acid therapies is into cerebrospinal fluid (CSF) because, at present, systemic delivery of siRNA-based therapeutics do not reach the CNS in meaningful concentrations due to the blood–brain barrier [5, 6].”
From Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid–siRNA conjugate administered into cerebrospinal fluid (2025) · cites this paper as [6]
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Metadata
- Authors
- DeVos, S. L., & Miller, T. M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Miller, Timothy M.
- Venue
- Neurotherapeutics
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 10
- Issue
- 3
- Pages
- 486-497
- ISSN
- 1878-7479 (ISSN-L)
- PMC
- PMC3701770
- OpenAlex
- W2093892225
- Cited by
- 164
- References
- 136
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 11 · 2023: 9 · 2022: 11 · 2021: 16 · 2020: 14 · 2019: 17 · 2018: 13 · 2017: 14 · 2016: 17 · 2015: 12 · 2014: 8 · 2013: 3
- FWCI
- 1.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neurotherapeutics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (P50AG005681)
- National Institute of Neurological Disorders and Stroke (NIH/NINDS K08NS074194, NIH/NINDS R01NS078398, K08NS074194, R01NS078398)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- antisense oligonucleotides, neurodegenerative diseases, RNA-targeted therapeutics, splicing modulation, microRNA inhibition, mouse models of human disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis
- MeSH terms
- Animals, Humans, RNA, Neuroprotective Agents, Neurodegenerative Diseases, Oligodeoxyribonucleotides, Antisense
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