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Cited by 121Genetic Neurodegenerative DiseasesAmyotrophic Lateral Sclerosis ResearchRNA Interference and Gene Delivery

Antisense oligonucleotide–mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles

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Friedrich, Jillian, Kordasiewicz, Holly B., O’Callaghan, Brennon, Handler, Hillary P., Wagener, Carmen, Duvick, Lisa, Swayze, Eric E., Rainwater, Orion +12 more·2018·JCI Insight
DOI 10.1172/jci.insight.123193PMC PMC6238731
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Abstract

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited ataxia caused by expansion of a translated CAG repeat encoding a glutamine tract in the ataxin-1 (ATXN1) protein. Despite advances in understanding the pathogenesis of SCA1, there are still no therapies to alter its progressive fatal course. RNA-targeting approaches have improved disease symptoms in preclinical rodent models of several neurological diseases. Here, we investigated the therapeutic capability of an antisense oligonucleotide (ASO) targeting mouse Atxn1 in Atxn1154Q/2Q-knockin mice that manifest motor deficits and premature lethality. Following a single ASO treatment at 5 weeks of age, mice demonstrated rescue of these disease-associated phenotypes. RNA-sequencing analysis of genes with expression restored to WT levels in ASO-treated Atxn1154Q/2Q mice was used to demonstrate molecular differences between SCA1 pathogenesis in the cerebellum and disease in the medulla. Finally, select neurochemical abnormalities detected by magnetic resonance spectroscopy in vehicle-treated Atxn1154Q/2Q mice were reversed in the cerebellum and brainstem (a region containing the pons and the medulla) of ASO-treated Atxn1154Q/2Q mice. Together, these findings support the efficacy and therapeutic importance of directly targeting ATXN1 RNA expression as a strategy for treating both motor deficits and lethality in SCA1.

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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).”

    From Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration (2023) · cites this paper as [53]

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Cited by

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Authors
Friedrich, J., Kordasiewicz, H. B., O’Callaghan, B., Handler, H. P., Wagener, C., Duvick, L., Swayze, E. E., Rainwater, O., Hofstra, B., Benneyworth, M., Nichols-Meade, T., Yang, P., Chen, Z., Ortiz, J. P., Clark, H. B., Öz, G., Larson, S., Zoghbi, H. Y., Henzler, C., & Orr, H. T.
Affiliations
  • University of Minnesota (US)
  • Ionis Pharmaceuticals (United States) (US)
  • Institute for Translational Neuroscience and
  • Department of Neuroscience, and
  • Howard Hughes Medical Institute (US)
Corresponding author
Orr, Harry T.
ORCID
Venue
JCI Insight
Publisher
American Society for Clinical Investigation
Published
2018-11-02
Volume
3
Issue
21
ISSN
2379-3708 (ISSN-L)
DOI
10.1172/jci.insight.123193
PMC
PMC6238731
OpenAlex
W2898693092
Cited by
121
References
7
Citations by year
2026: 4 · 2025: 3 · 2024: 13 · 2023: 24 · 2022: 20 · 2021: 29 · 2020: 18 · 2019: 10
FWCI
6.49
Type
journal article
Language
en
Open access
Locations
  • JCI Insight (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • NIH/NINDS (R37 NS022920, R37NS027699)
  • NIH-NIBIB (P41 EB015894)
  • NIH (P30 NS076408, R37 NS022920,R37NS027699,P41 EB015894,P30 NS076408)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
spinocerebellar ataxia type 1, ataxin-1, antisense therapy, CAG repeat expansion, survival extension, gene expression profiling, cerebellum, medulla, brainstem, neurochemical abnormalities, motor impairment, RNA interference
MeSH terms
Ataxin-1, Animals, Female, Male, Nerve Tissue Proteins, Magnetic Resonance Spectroscopy, Phenotype, Survival Analysis, Oligonucleotides, Antisense, Sequence Analysis, RNA, Neurodegenerative Diseases, Spinocerebellar Ataxias, Mice, Transcriptome

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