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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 3

Recovery of SCA1-like phenotypes in Atxn1154Q/2Q mice receiving ASO353 by i.c.v. injection at 5 weeks of age.

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Recovery of SCA1-like phenotypes in Atxn1154Q/2Q mice receiving ASO353 b...
Mice were administered ASO353 or vehicle (saline) by bolus i.c.v. injection at 5 weeks. (A) Motor performance on a rotarod between ages 5 weeks and 27 weeks. Data are presented as the mean ± SEM. **P < 0.01, ***P < 0.001, 1-way ANOVA. (B) Motor performance on a balance beam at ages 15 weeks and 26 weeks. Data are presented as the mean ± SEM. **P < 0.01, ***P < 0.001, 1-way ANOVA. (C) Survival, plotted as Kaplan-Meyer curves, for mice receiving a bolus i.c.v. injection of 500 μg ASO353 or vehicle (saline) at 5 weeks. ***P = 0.0001, log-rank Mantel-Cox test; P = 0.0005, Gehan-Breslow-Wilcoxon test. (D) i.c.v. injection of ASO353 fails to improve the failure-to-gain weight phenotype in Atxn1154Q/2Q mice; WT C57BL/6 uninjected (n = 23), WT C57BL/6 vehicle (n = 16), Atxn1154Q/2Q uninjected (n = 19), Atxn1154Q/2Q vehicle (n = 15), and Atxn1154Q/2Q ASO353 (n = 12).

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