Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease that causes progressive loss of motor coordination, respiratory issues, and eventual death. SCA1 is caused by expansion of the polyglutamine repeat region in the ATXN1 gene. Although mutant ATXN1 is expressed ubiquitously, it affects primarily Purkinje cells (PCs). Currently there are no disease modifying treatments; however, previous work has shown the potential of gene therapy, specifically RNAi, as a potential modality. Genome editing offers a possible treatment for these patients but has yet to be evaluated in SCA1 models. I hypothesize that Clustered Regularly Interspaced Short Palidromic Repeats (CRISPR)-Cas editing will reduce ATXN1 and be therapeutically beneficial. To test this, I first selected gene editing strategies in vitro and investigated multiple mouse models to identify an optimal in vivo system. I found my single gRNA strategy targeting at the exon-exon junction and a dual gRNA strategy flanking the CAG repeat region reduced ATXN1 levels by approximately 56% in HEK293 cells. I performed two behavior studies in mice modeling SCA1 with expanded ATXN1 CAG repeats. Though the first attempt was unsuccessful, I leveraged the data collected to alter multiple aspects of our strategy such as timing of delivery and the mouse model used. During characterization of mouse models, I assessed the number of transgenes harbored in the B05 model of SCA1. Despite having 5 copies of the human mutant transgene, the single gRNA strategy led to a 20% reduction of ATXN1. This resulted in amelioration of behavior deficits without increases in inflammatory markers; however, I did not observe rescue of molecular pathology. Importantly, the editing outcomes were consistent in induced pluripotent stem cells (iPSC) neurons derived from patients with SCA1, promoting the translatability of the approach to patients. I confirmed dual gRNA editing in mice but saw a low deletion frequency; less than 1% of the ATXN1 loci evaluated had a full-length deletion. This thesis successfully demonstrates the validity of a Cas9 meditated therapeutic approach for SCA1 while simultaneously highlighting the difficulties in transgenic animal models faithfully representing gene editing outcomes.