Heart failure remains an enormous socio-economic burden and the development of novel therapeutic strategies tackling fundamental concepts of cardiobiology are urgently needed. CRISPR/Cas9 mediated endogenous gene activation (CRISPRa) allows for targeted transcription control without introducing DNA strand breaks or changing the genetic code, respectively. For this, we use enzymatically inactive Cas9 (dCas9) proteins fused to transcription activation domains (VPR) programmable by a 20-nucleotide guide RNA (gRNA), targeted to the 5’ upstream transcriptional start site region of genes of interest to induce their expression. Using this system, we previously investigated the role of the transcription factor Krüppel-like factor 15 (KLF15) in pathological cardiac remodeling. We demonstrated CRISPRa mediated re-activation of KLF15 upon pressure overload and in induced pluripotent stem cell (hiPSC) derived cardiomyocyte based engineered human myocardium models resulting in reduced cardiomyocyte remodeling and heart failure progression. These models are useful tools for proof-of-concept studies, however clinical translation of this approach requires the development of deliverable vectors. We designed mini-dCas9 variants fused to a minimized VPR domain and tested these vectors in human HEK293T cells and mouse C2C12 myoblasts to activate KLF15. We observed expression of these vectors by qPCRs and immunoblotting, confirmed a nucleus enriched abundance of the programmable transcription factor together with a 3-fold KLF15 activation in HEK293T cells (n = 4, p < 0.01) and 15-fold activation in C2C12 cells (n = 3, p < 0.01) using the developed vectors and a single identified mouse or human gRNA, respectively. Importantly, the gene activation strength with mini-dCas9VPR was comparable with our data using Streptococcus pyogenes dCas9VPR overall indicating comparability of the gene activation systems and validation strategies. Additionally, we developed lentiviral vectors to test these constructs in hard-to-transfect cell types and in human myocardial slices confirming applicability of these vectors in these model systems. Finally, we generated adeno-associated virus (rAAV2/9) particles expressing mini-dCas9VPR under TNNT2 promoter control together with the identified KLF15 gRNA to enhance KLF15 expression specifically in cardiomyocytes. These plasmids were transfected, and vectors were transduced into hiPSC-cardiomyocytes and KLF15 expression was checked by qPCR 2-days post-transfection or 7-days post-transduction, respectively. We observed 2-fold and 3.5-fold transcriptional activation (n (transfection) = 4, p < 0.01, n (transduction) = 2) compared to vectors expressing a non-targeted gRNA or non-transduced hiPSC-cardiomyocytes. In summary, we present Cas9-based programmable transcription factors enabling us to control transcription in the diseased heart and demonstrated the biological relevance of such an approach with anti-remodeling effects mediated by KLF15 re-normalization in vivo and in vitro. Furthermore, we developed an AAV-mediated gene therapy concept for the use of CRISPRa as a blueprint for targeted endogenous gene activity control useful for the identification of target candidate genes in basic cardiovascular science and for the translation of novel therapeutic concepts.