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

3 Citations (Scopus)

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

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Spinocerebellar Ataxias
Antisense Oligonucleotides
Transcriptome
Neurological Models
RNA
RNA Sequence Analysis
Cerebellar Diseases
Pons
Ataxia
Glutamine
Cerebellum
Brain Stem
Ataxin-1
Rodentia
Magnetic Resonance Spectroscopy
Therapeutics
Phenotype
Gene Expression

Keywords

  • Drug therapy
  • Neurodegeneration
  • Neuroscience

PubMed: MeSH publication types

  • Journal Article

Cite this

Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles. / Friedrich, Jillian; Kordasiewicz, Holly B.; O'Callaghan, Brennon; Handler, Hillary P.; Wagener, Carmen; Duvick, Lisa; Swayze, Eric E.; Rainwater, Orion; Hofstra, Bente; Benneyworth, Michael; Nichols-Meade, Tessa; Yang, Praseuth; Chen, Zhao; Ortiz, Judit Perez; Clark, H. Brent; Oz, Gulin; Larson, Sarah; Zoghbi, Huda Y.; Henzler, Christine; Orr, Harry T.

In: JCI Insight, Vol. 3, No. 21, 02.11.2018.

Research output: Contribution to journalArticle

Friedrich, J, Kordasiewicz, HB, O'Callaghan, B, Handler, HP, Wagener, C, Duvick, L, Swayze, EE, Rainwater, O, Hofstra, B, Benneyworth, M, Nichols-Meade, T, Yang, P, Chen, Z, Ortiz, JP, Clark, HB, Oz, G, Larson, S, Zoghbi, HY, Henzler, C & Orr, HT 2018, 'Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles', JCI Insight, vol. 3, no. 21. https://doi.org/10.1172/jci.insight.123193
Friedrich, Jillian ; Kordasiewicz, Holly B. ; O'Callaghan, Brennon ; Handler, Hillary P. ; Wagener, Carmen ; Duvick, Lisa ; Swayze, Eric E. ; Rainwater, Orion ; Hofstra, Bente ; Benneyworth, Michael ; Nichols-Meade, Tessa ; Yang, Praseuth ; Chen, Zhao ; Ortiz, Judit Perez ; Clark, H. Brent ; Oz, Gulin ; Larson, Sarah ; Zoghbi, Huda Y. ; Henzler, Christine ; Orr, Harry T. / Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles. In: JCI Insight. 2018 ; Vol. 3, No. 21.
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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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AU - Hofstra, Bente

AU - Benneyworth, Michael

AU - Nichols-Meade, Tessa

AU - Yang, Praseuth

AU - Chen, Zhao

AU - Ortiz, Judit Perez

AU - Clark, H. Brent

AU - Oz, Gulin

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