Abstract: Compositions include CRISPR RNAs, guide RNAs, and nucleic acid molecules encoding the same. Vectors and host cells comprising the nucleic acid molecules are also provided. Further provided are RNA-guided nuclease (RGN) systems for cleaving a mutHTT allele, wherein the RGN system comprises an RNA-guided nuclease and a guide RNA. The compositions find use in cleaving or modifying a mutHTT allele, and/or modifying the expression of a mutHTT allele. The compositions are additionally useful for treating Huntington's disease (HD), particularly in an allele-specific manner.