Transcriptional enhancement as therapeutic approach of coagulation factor VII promoter mutations

The main scope of the proposed project is to explore the ability of engineered Transcription Factors (eTFs) to rescue gene expression of F7 gene in the presence of mutations impairing gene transcription. More specific objectives are: -to identify eTFs able to enhance F7 gene transcription in human liver cell lines, -to identify eTFs able to rescue F7 gene transcription affected by mutations in cellular models, -to generate mouse models of F7 promoter mutations -to produce liver specific Adeno-Associated Virus (AAV) for the delivery of eTFs -to provide the proof-of-principle for the eTFs mediated rescue of F7 gene expression in mouse models. We expect to provide in vitro and in vivo insights into the ability of eTFs to rescue naturally occurring F7 promoter mutations and increase FVII expression levels. This method might suggest innovative therapeutic approaches for coagulation factor deficiencies or other human diseases caused by impaired gene transcription.