Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Antisense oligonucleotide–mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles
Jillian Friedrich, … , Christine Henzler, Harry T. Orr
Jillian Friedrich, … , Christine Henzler, Harry T. Orr
Published November 2, 2018
Citation Information: JCI Insight. 2018;3(21):e123193. https://doi.org/10.1172/jci.insight.123193.
View: Text | PDF
Research Article Neuroscience

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

  • Text
  • PDF
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.

Authors

Jillian Friedrich, Holly B. Kordasiewicz, Brennon O’Callaghan, Hillary P. Handler, Carmen Wagener, Lisa Duvick, Eric E. Swayze, Orion Rainwater, Bente Hofstra, Michael Benneyworth, Tessa Nichols-Meade, Praseuth Yang, Zhao Chen, Judit Perez Ortiz, H. Brent Clark, Gülin Öz, Sarah Larson, Huda Y. Zoghbi, Christine Henzler, Harry T. Orr

×

Figure 1

Reduction of Atxn1 RNA by Atxn1 ASO353 in brain regions of Atxn166Q/2Q mice affected by SCA1.

Options: View larger image (or click on image) Download as PowerPoint
Reduction of Atxn1 RNA by Atxn1 ASO353 in brain regions of Atxn166Q/2Q m...
500 μg Atxn1 ASO or vehicle was delivered by bolus i.c.v. injection to 5-week-old Atxn166Q/2Q mice. Atxn1 RNA analyzed by qPCR at 2, 12, and 18 weeks after i.c.v. injection. (A) Atxn1 RNA analyzed from the cerebellum; 2-week ASO and vehicle (n = 6), 12-week ASO and vehicle (n = 3), 18-week ASO (n = 5), 18-week vehicle (n = 7). (B) Atxn1 RNA analyzed from the medulla; 2-week ASO and vehicle (n = 6), 12-week ASO and vehicle (n = 3), 18-week ASO (n = 5), 18-week vehicle (n = 7). (C) Atxn1 RNA analyzed from the pons; 2 week and 12-week ASO and vehicle (n = 3), 18-week ASO (n = 5), 18-week vehicle (n = 7). (D) Atxn1 RNA analyzed from the cerebral cortex; 2-week ASO and vehicle (n = 6), 12-week ASO and vehicle (n = 3), 18-week ASO (n = 5), 18-week vehicle (n = 7). Data are presented as mean ± SEM. **P < 0.01, ***P < 0.001, ****P < 0.0001, 2-way ANOVA.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts