Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models
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Mutations in superoxide dismutase 1 (SOD1) are responsible for 20% of familial ALS. Given the gain of toxic function in this dominantly inherited disease, lowering SOD1 mRNA and protein is predicted to provide therapeutic benefit. An early generation antisense oligonucleotide (ASO) targeting SOD1 was identified and tested in a phase I human clinical trial, based on modest protection in animal models of SOD1 ALS. Although the clinical trial provided encouraging safety data, the drug was not advanced because there was progress in designing other, more potent ASOs for CNS application. We have developed next-generation SOD1 ASOs that more potently reduce SOD1 mRNA and protein and extend survival by more than 50 days in SOD1G93A rats and by almost 40 days in SOD1G93A mice. We demonstrated that the initial loss of compound muscle action potential in SOD1G93A mice is reversed after a single dose of SOD1 ASO. Furthermore, increases in serum phospho-neurofilament heavy chain levels, a promising biomarker for ALS, are stopped by SOD1 ASO therapy. These results define a highly potent, new SOD1 ASO ready for human clinical trial and suggest that at least some components of muscle response can be reversed by therapy.
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ASOs can specifically alter levels and/or processing of a variety of proteins involved in neurodegenerative diseases, most of which have been the disease-causing protein itself.
“Due to the precision afforded by complementary binding of an ASO to its target transcript of interest, ASOs have emerged as an invaluable tool in specifically altering levels and/or processing of a variety of proteins involved in neurodegenerative diseases, most of which have been the disease-causing protein itself (38, 51–54).”
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- Authors
- McCampbell, A., Cole, T., Wegener, A. J., Tomassy, G. S., Setnicka, A., Farley, B. J., Schoch, K. M., Hoye, M. L., Shabsovich, M., Sun, L., Luo, Y., Zhang, M., Thankamony, S., Salzman, D. W., Cudkowicz, M., Graham, D. L., Bennett, C. F., Kordasiewicz, H. B., Swayze, E. E., & Miller, T. M.
- Affiliations
- Biogen (United States) (US)
- Ionis Pharmaceuticals (United States) (US)
- Washington University in St. Louis (US)
- Harvard University (US)
- Corresponding author
- Miller, Timothy M.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2018-07-16
- Volume
- 128
- Issue
- 8
- Pages
- 3558-3567
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC6063493
- OpenAlex
- W2884390718
- Cited by
- 279
- References
- 46
- Citations by year
- 2026: 30 · 2025: 36 · 2024: 48 · 2023: 35 · 2022: 32 · 2021: 30 · 2020: 42 · 2019: 22 · 2018: 4
- FWCI
- 16.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- Biogen
- Ionis Pharmaceuticals
- National Institutes of Health (50 and)
- National Institute of Neurological Disorders and Stroke (U01NS084970, R01NS078398)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- antisense oligonucleotides, amyotrophic lateral sclerosis, SOD1, SOD1 G93A mice, familial ALS, compound muscle action potential, neurofilament heavy chain, biomarkers, survival extension, ALS therapeutics
- MeSH terms
- Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Disease Models, Animal, Humans, Superoxide Dismutase, Muscle, Skeletal, Oligodeoxyribonucleotides, Antisense, Rats, Rats, Transgenic
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