Abstract Rett Syndrome is a devastating neurodevelopmental disease caused by loss of function mutations of the MeCP2 gene, located on the X chromosome. Affecting nearly 20,000 girls in the US and EU, disease manifestation is due to neuronal mosaicism caused by random X inactivation: half Rett patient neurons express the wild type (WT) gene on the active X chromosome (Xa), while the other half express the mutated (MT) MeCP2 gene, with the WT MeCP2 silenced on the inactive X chromosome (Xi). Epigenome editing using CRISPR systems is a potential targeted therapy allowing reactivation of the silenced but functional MeCP2 gene on Xi. The epigenetic editor is comprised of a catalytically dead Cas (dCas) fused with effector proteins, such as the DNA demethylase Ten-eleven translocation (TET) protein to demethylate and thereby activate target genes. Epitor Therapeutics is developing novel epigenome editing tools to treat Rett Syndrome. Our editor combines CasNano, an ultracompact CRISPR protein retaining robust DNA targeting, fused to TETmini, a miniature yet potent TET demethylase domain. Compact enough to package into a single adeno- associated virus (AAV), this epigenetic editor enables targeted delivery of epigenome editing machinery to the brain. Our proposed strategy includes optimizing the epigenetic editor components for DNA targeting ability and specificity (Aim 1); assessing in vitro target validation in Rett patient iPSC-derived neurons and off-target analysis in human embryonic stem cells (Aim 2); and assessing pharmacology and phenotypic efficacy of the AAV9 encapsulating dCasNano-TETmini epigenetic editors in a Rett syndrome, female MeCP2-humanized mouse model (Aim 3). If successful, this would represent the first epigenetic editing treatment for disorders of the CNS, overcoming key delivery barriers that have blocked development of targeted epigenetic therapies.