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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 7

ASO treatment effects on neurochemicals in the cerebella and brainstems in Atxn1154Q/2Q mice.

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ASO treatment effects on neurochemicals in the cerebella and brainstems ...
(A and D) Voxel placement and spectral quality in the cerebellum and brainstem. T2-weighted images and localized proton MR spectra (LASER, TE = 15 ms, TR = 5 s) are shown for an ASO353-treated Atxn1154Q/2Q mouse. (B, C, E, and F) Myo-inositol (Ins) and total choline (tCho) concentrations in the cerebella (B and C) and brainstems (E and F) of ASO353-treated Atxn1154Q/2Q mice, vehicle-treated Atxn1154Q/2Q mice, and vehicle-treated WT mice at 18 and 28 weeks of age. Sample sizes in B and E are as follows: ASO-treated Atxn1154Q/2Q mice (n = 11), vehicle-treated Atxn1154Q/2Q mice (n = 12), and WT mice (n = 11). Sample sizes in C and F are as follows: ASO-treated Atxn1154Q/2Q mice (n = 16), vehicle-treated Atxn1154Q/2Q mice (n = 15), and WT mice (n = 15). In the box-and-whisker plots, the bounds of the boxes represent 25th to 75th percentiles, the line in the box is the median, and the whiskers extend to the minimum and maximum values. Group means for neurochemical concentrations were compared with 1-way ANOVA, and P values were corrected for multiple comparisons using the Tukey Method. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

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