Antisense oligonucleotide therapy for neurodegenerative disease
Open accessAbstract
Neurotoxicity from accumulation of misfolded/mutant proteins is thought to drive pathogenesis in neurodegenerative diseases. Since decreasing levels of proteins responsible for such accumulations is likely to ameliorate disease, a therapeutic strategy has been developed to downregulate almost any gene in the CNS. Modified antisense oligonucleotides, continuously infused intraventricularly, have been demonstrated to distribute widely throughout the CNS of rodents and primates, including the regions affected in the major neurodegenerative diseases. Using this route of administration, we found that antisense oligonucleotides to superoxide dismutase 1 (SOD1), one of the most abundant brain proteins, reduced both SOD1 protein and mRNA levels throughout the brain and spinal cord. Treatment initiated near onset significantly slowed disease progression in a model of amyotrophic lateral sclerosis (ALS) caused by a mutation in SOD1. This suggests that direct delivery of antisense oligonucleotides could be an effective, dosage-regulatable means of treating neurodegenerative diseases, including ALS, where appropriate target proteins are known.
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A number of clinical trials are now in progress for treatments of serious neurological diseases that rely on continuous infusion of ASOs into the CSF.
“Furthermore, a number of clinical trials are now in progress for treatments of serious neurological diseases that rely on continuous infusion of ASOs into the CSF.27,28”
From Lipid Nanoparticle Delivery of siRNA to Silence Neuronal Gene Expression in the Brain (2013) · cites this paper as [28]
The Discussion (page unavailable) describes a Phase I trial in human familial ALS patients as planned, not in progress, and says safety studies were underway in animals. The Results describe continuous ASO infusion in rats and a nonhuman primate, but the paper does not report multiple ongoing clinical trials. (LLM, conf=0.88)
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Experimental — accuracy not yet measuredICV infusion of free ASOs against superoxide dismutase by osmotic pump at 100 μg/day per rat over 28 days (total of 2.8 mg of ASO) resulted in ~50% superoxide dismutase mRNA silencing.
“With regard to dose levels, ICV infusion of free ASOs against superoxide dismutase by osmotic pump at 100 µg/day per rat over 28 days (total of 2.8 mg of ASO) resulted in ˜50% superoxide dismutase mRNA silencing.28”
From Lipid Nanoparticle Delivery of siRNA to Silence Neuronal Gene Expression in the Brain (2013) · cites this paper as [28]
The Results and Figure 3 caption describe SOD1-targeted ASOs infused into rats’ lateral ventricles by osmotic pump for 28 days at the stated daily dose. But the Results report SOD1 mRNA at 25–40% of normal (a 60–75% reduction); the approximately 50% reduction was in SOD1 protein, not mRNA. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredASO injection into CSF is a therapeutically viable approach that was initiated 14 years ago and validated to yield effective delivery to neurons and glial cells throughout the rodent and non-human primate nervous systems.
“ASO injection into cerebral spinal fluid (CSF) is a therapeutically viable approach that was initiated 14 years ago13 and validated to yield effective delivery to neurons and glial cells throughout the rodent13 and non-human primate14 nervous systems.”
From Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB (2021) · cites this paper as [13]
Optimized ASOs to other targets have previously been shown to yield dose dependent target RNA suppression to 5% of initial level.
“optimized ASOs to other targets have previously been shown to yield dose dependent target RNA suppression to 5% of initial level13,14,48.”
From Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB (2021) · cites this paper as [13]
Similar ASO mRNA-targeted approaches have improved disease phenotypes in rat models of SOD1-related ALS, mouse models of Huntington's disease and FTDP-17, and in C9ORF72 patient-derived cell lines.
“Similar ASO mRNA-targeted approaches have improved disease phenotypes in rat models of superoxide dismutase 1 (SOD1)-related ALS (17), mouse models of Huntington’s disease (18) and FTDP-17 (19), and in C9ORF72 patient-derived cell lines (20, 21).”
From Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy (2017) · cites this paper as [17]
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- Authors
- Smith, R. A.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Smith, R. A.
- ORCID
- Smith, R. A.
- Venue
- Journal of Clinical Investigation
- Published
- 2006-08-01
- Volume
- 116
- Issue
- 8
- Pages
- 2290-2296
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1518790
- OpenAlex
- W2149414920
- Cited by
- 506
- References
- 63
- Citations by year
- 2026: 15 · 2025: 19 · 2024: 31 · 2023: 28 · 2022: 27 · 2021: 24 · 2020: 39 · 2019: 21 · 2018: 30 · 2017: 36 · 2016: 32 · 2015: 22 · 2014: 26 · 2013: 35 · 2012: 32
- FWCI
- 10.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- Journal of Clinical Investigation (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- ALS Association
- Muscular Dystrophy Association
- Ludwig Institute for Cancer Research
- National Institutes of Health (NIH K12, NS27036)
- National Institute of Neurological Disorders and Stroke (NS 27036, R37NS027036, R01NS027036)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- antisense oligonucleotides, neurodegenerative diseases, amyotrophic lateral sclerosis, SOD1, superoxide dismutase 1, gene downregulation, protein misfolding, disease progression
- MeSH terms
- Superoxide Dismutase-1, Animals, Base Sequence, Fibroblasts, Macaca mulatta, RNA, Messenger, Superoxide Dismutase, Ventricular Function, Oligonucleotides, Antisense, Motor Neuron Disease, Protein Folding, Neurodegenerative Diseases, Rats
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