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

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
• Journal: JCI insight (JCI Insight) Vol. 3 Issue 21 (11 02 2018) ISSN: 2379-3708 [Electronic] United States
• PMID: 30385727 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ataxin-1
• Atxn1 protein, mouse
• Nerve Tissue Proteins
• Oligonucleotides, Antisense

Topics

• Animals
• Ataxin-1 (drug effects, metabolism)
• Female
• Magnetic Resonance Spectroscopy (methods)
• Male
• Mice
• Nerve Tissue Proteins (drug effects, metabolism)
• Neurodegenerative Diseases (drug therapy, genetics)
• Oligonucleotides, Antisense (administration & dosage, adverse effects, therapeutic use)
• Phenotype
• Sequence Analysis, RNA (methods)
• Spinocerebellar Ataxias (classification, diagnostic imaging, drug therapy, genetics)
• Survival Analysis
• Transcriptome