4.7 Article

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

Journal

JCI INSIGHT
Volume 3, Issue 21, Pages -

Publisher

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.123193

Keywords

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Funding

  1. NIH/National Institute of Neurological Disorders and Stroke (NIH/NINDS) [R37 NS022920]
  2. National Ataxia Foundation Pioneer Award
  3. Wallin Neuroscience Discovery Award
  4. NIH/NINDS [R37NS027699]
  5. Howard Hughes Medical Institute
  6. Jay D. Schlueter Ataxia Research Fund
  7. National Institute of Biomedical Imaging and Bioengineering [P41 EB015894]
  8. Institutional Center Cores for Advanced Neuroimaging [P30 NS076408]
  9. W.M. Keck Foundation

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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 Atxn1(1540/2Q)-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 Atxn1(154Q/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 Atxn1(154Q/2Q) mice were reversed in the cerebellum and brainstem (a region containing the pons and the medulla) of ASO-treated Atxn1(154Q/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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