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

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, Gulin Oz, Sarah Larson, Huda Y. Zoghbi, Christine Henzler, Harry T Orr

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
JournalJCI Insight
Volume3
Issue number21
DOIs
StatePublished - Nov 2 2018

Keywords

  • Drug therapy
  • Neurodegeneration
  • Neuroscience

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    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., Oz, G., Larson, S., Zoghbi, H. Y., Henzler, C., & Orr, H. T. (2018). Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles. JCI Insight, 3(21). https://doi.org/10.1172/jci.insight.123193