Abstract: Provided in some aspects are compositions, such as DNA-targeting systems, fusion proteins, guide RNAs (gRNAs), and pluralities and combinations thereof, that bind to or target a frataxin (FXN) locus. In particular, the present disclosure relates to the modulation of expression of the FXN gene. In some aspects, the present disclosure also relates to poly nucleotides, vectors, cells and pluralities and combinations thereof, that encode or comprise the DNA-targeting systems, fusion proteins, gRNAs or pluralities or combinations thereof, and methods and uses related to the provided compositions, for example, in modulating the expression of FXN, and/or in the treatment or therapy of diseases or disorders that involve the activity, function or expression of FXN, such as Friedreich's Ataxia (FA).

Abstract: Provided in some aspects are compositions, such as DNA-targeting systems, fusion proteins, guide RNAs (gRNAs), and pluralities and combinations thereof, that bind to or target a methyl-CpG-binding protein 2 (MeCP2) locus. In particular, the present disclosure relates to the modulation of expression of the MeCP2 gene. In some aspects, also provided are polynucleotides, vectors, cells and pluralities and combinations thereof, that encode or comprise the DNA-targeting systems, fusion proteins, gRNAs or pluralities or combinations thereof, and methods and uses related to the provided compositions, for example, in modulating the expression of MeCP2, and/or in the treatment or therapy of diseases or disorders that involve the activity, function or expression of MeCP2, such as Rett syndrome.

Abstract: Provided in some aspects are epigenetic-modifying DNA-targeting systems, such as CRISPR-Cas/guide RNA (gRNA) systems for the transcriptional repression of genes to promote a cellular phenotype that leads to reduction of low-density lipoprotein (LDL). In some embodiments, the epigenetic-modifying DNA-targeting systems bind to or target a target site of at least one gene or regulatory element thereof that regulate LDL. In some embodiments, the systems are multiplexed systems that bind to or target a target site in at least two genes or regulatory elements thereof. Also provided herein are methods and uses related to the provided epigenetic-modifying DNA targeting systems in connection with treatments for cardiovascular disease and familial hypercholesterolemia.