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The repeats undergo bidirectional transcription to produce sense and antisense repeat RNA species, which are translated into dipeptide repeat proteins (DPRs). As toxicity has been associated with both sense and antisense repeat-derived RNA and DPRs, targeting both strands may provide the most effective therapeutic strategy. CRISPR-Cas13 systems mature their own guide arrays, allowing targeting of multiple RNA species from a single construct. We show CRISPR-Cas13d variant CasRx effectively reduces overexpressed <jats:italic>C9orf72<\/jats:italic> sense and antisense repeat transcripts and DPRs in HEK cells. In <jats:italic>C9orf72<\/jats:italic> patient-derived iPSC-neuron lines, CRISPR-CasRx reduces endogenous sense and antisense repeat RNAs and DPRs and protects against glutamate-induced excitotoxicity. AAV delivery of CRISPR-CasRx to two distinct <jats:italic>C9orf72<\/jats:italic> repeat mouse models significantly reduced both sense and antisense repeat-containing transcripts. 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