Development and Application of Optimized Cardio-Specific AdVector-based Systems for In Situ Establishment of Biological Pacemakers

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Our project addresses the establishment of a "Biological Cardiac Pacemaker" for future therapy of cardiac diseases summarized under the term "Sick-Sinus-Syndrome". We intend to create a biological pacemaker via direct reprogramming of working cardiomyocytes based on the introduction of optimized programming factor combinations. They will be introduced into the target cells via our SMART adenovirus technology, which combines highest specificity, efficacy and safety by tailoring high capacity Ad vectors to bi-specific adaptor proteins, pseudotyping and magnetic nanoparticles. The envisaged approaches allow in situ alterations of cells in vivo. Proof-of-principle will be achieved initially in vitro relying on cultured murine PSC derived cardiomyocytes. Thereby, murine PSC derived pacemaker cells generated via our established forward programming approach will serve as a reference for physiological and functional parameters. The concept will then be translated to a pre-clinical model relying on transgenic mice bearing an experimentally induced Sick-Sinus-Syndrome as well as an ex vivo situation using pig heart slice cultures. Factors, recently newly identified via RNAseq of forward programmed murine pacemaker cells will be included with respect to their applicability in direct reprogramming. The described concept is scientifically unique and of highest clinical relevance.