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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.
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Research Article Neuroscience

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

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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.

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

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Figure 4

Differentially expressed genes in the cerebella, pontes, and medullae of Atxn1154Q/2Q mice receiving vehicle or ASO353 by i.c.v. (A) Genes differentially expressed in vehicle-treated WT versus vehicle-treated Atxn1154Q/2Q mice from the cerebellum at 18 weeks, the pons at 18 and 28 weeks, and the medulla at 18 and 28 weeks.

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Differentially expressed genes in the cerebella, pontes, and medullae of...
The black portion of the bars depicts the number of genes downregulated and the gray portion of the bars depicts the number of genes upregulated in vehicle-treated Atxn1154Q/2Q mice. (B) Genes differentially expressed in vehicle-treated Atxn1154Q/2Q versus ASO353-treated Atxn1154Q/2Q mice from the cerebellum at 18 weeks, the pons at 18 and 28 weeks, and the medulla at 18 and 28 weeks. The black portion of the bars depicts the number of genes downregulated and the gray portion of the bars depicts the number of genes upregulated in ASO353-treated Atxn1154Q/2Q mice. In A and B, numbers above bars indicate the number genes with differential expression. (C and D) GSEA of the Magenta module compared with differentially expressed gene lists from the cerebella of 18-week-old and medullae of 28-week-old Atxn1154Q/2Q mice, respectively. Significance was determined by the observed enrichment score compared to a set of null scores generated by permuting the gene ranked order 10,000 times.

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