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Safely and efficiently controlling gene expression is a long-standing goal of biomedical research, and the recently discovered bacterial CRISPR/Cas system can be harnessed to create powerful tools for epigenetic editing. Current state-of-the-art systems consist of a deactivated-Cas9 nuclease (dCas9) fused to epigenetic effector motifs/domains, along with a guide RNA (gRNA) which defines the genomic target. Such systems have been used to safely and effectively silence or activate a specific gene target under a variety of circumstances. Adeno-associated virus (AAV) vectors are the therapeutic platform of choice for delivery of genetic cargoes; nevertheless, their small packaging capacity is not suitable for the delivery of large constructs, including most CRISPR/dCas9-effector systems. To circumvent this, many AAV-based CRISPR/Cas tools are delivered separately from two viral cassettes. However, this approach requires higher viral payloads and usually is less efficient. Here we develop a compact dCas9-based repressor system packaged within a single, optimized AAV vector. The system uses a smaller dCas9 variant derived fromStaphylococcus aureus(Sa). A novel repressor was engineered by fusing the small transcription repression domain (TRD) from MeCP2 with the KRAB repression domain. The final dSaCas9-KRAB-MeCP2(TRD) construct can be efficiently packaged, along with its associated gRNA, into AAV particles. Using reporter assays, we demonstrate that the platform is capable of robustly and sustainably repressing the expression of multiple genes-of-interest, bothin vitroandin vivo. Most relevantly, we successfully silencedAPOE, the primary genetic risk factor for late onset Alzheimer’s disease (LOAD). This new platform will broaden the CRISPR/dCas9 toolset available for transcriptional manipulation of gene expression in research and therapeutic settings.