Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant disorder caused by an abnormal expansion of the trinucleotide CAG in the coding region of the ATXN2 gene. This is translated into an expanded polyglutamine tract in the ataxin-2 protein, leading to a gain of toxic function affecting especially the neurons. Besides the pathogenic mechanisms triggered by ataxin-2 dysfunction, previous studies showed that abnormally expanded CAG repeats display toxicity already at the RNA level, contributing to disease pathogenesis. Considering these data, it is important to develop therapeutic approaches that act at the most upstream point of the pathogenic cascade. The present work takes advantage of SCA2 iPSC lines to develop CRISPR-Cas-based strategies targeting ATXN2. We have designed a CRISPRi strategy whereby inactive Cas9 is fused to a transcriptional repressor, KRAB, and is directed to the ATXN2 promoter, hindering the activity of the transcription machinery. An excision strategy directing Cas9 nuclease to two sites of the ATXN2 gene, excising the intervening region. Finally, a traditional CRISPR-Cas9 strategy directs Cas9 to an early site of the ATXN2 gene, compromising the integrity of the reading frame by an indel mutation. CRISPR-Cas isogenic lines were differentiated into neurons and specific pathological traits, such as ataxin-2 levels, Ca2+ disturbance, neuronal ramification, and survival were assessed to determine the impact of CRISPR-mediated approaches towards the rescue of neuronal function. As the CRISPR toolbox expands, silencing the pathogenic expression of ATXN2 seems to be a promising therapeutic approach for the treatment or even cure of SCA2 patients.