Portal de Periódicos da CAPES

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

2018; American Society for Clinical Investigation; Volume: 3; Issue: 21 Linguagem: Inglês

10.1172/jci.insight.123193

2379-3708

Jillian Friedrich, Holly Kordasiewicz, Brennon O’Callaghan, Hillary P. Handler, Carmen Wagener, Lisa Duvick, Eric E. Swayze, Orion Rainwater, Bente Hofstra, Michael A. Benneyworth, Tessa Nichols‐Meade, Praseuth Yang, Chen Zhao, Judit Perez Ortiz, H. Brent Clark, Gülin Öz, Sarah N. Larson, Huda Y. Zoghbi, Christine Henzler, Harry T. Orr,

Mitochondrial Function and Pathology

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.