Therapeutic effects of ASO-mediated reduction of Atxn1 in a SCA1 Mouse Mode: Proof of concept with distinct disease-associated transcriptome profiles in cerebellum and medulla

RNA-targeting approaches have improved disease symptoms in preclinical rodent models of several neurological diseases. Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited ataxia caused by expansion of a polyglutamine tract in the encoded protein Ataxin-1 (ATXN1). Despite advances in understanding this CAG repeat/polyglutamine expansion disease, there are still no therapies to alter its progressive fatal course. Here we investigate the therapeutic capability of an antisense oligonucleotide (ASO) targeting mouse Atxn1 in Atxn 1 154Q/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. In addition, RNA-seq on vehicle-treated Atxn1 154Q/2Q and ASO-treated Atxn1 154Q/2Q mice were used to demonstrate molecular differences between SCA1 pathogenesis in the cerebellum that underlies ataxia with disease in the medulla associated with lethality. Together, these findings support the efficacy and therapeutic importance of directly targeting ATXN1 expression as a strategy to rescue both motor deficits and lethality seen in SCA1. Medulla and pons (18 and 28 week mice) and cerebella (18 week only) mRNA profiles of wild type (WT) and Atxn1[82Q] knockin mice were generated by deep sequencing using Illumina HiSeq 2500. Atxn1[82Q] knockin mice mRNA profiles were assessed with and without treatment with an anti-sense oligonucleotide targeting Atxn1.