mRNA biological pacemaker

For those with symptomatic bradyarrhythmia, implantable pacemakers are the only treatment. While effective, the device therapy is burdened with complications directly related to the indwelling hardware such as device malfunction and infection. As an alternative to device pacing, biological pacemakers offer an original approach to cardiac pacing. In this proposed project, we will test the idea that mRNA-based transgene expression suffices to reprogram ventricular myocytes to pacemaker cells in vitro and in situ, thereby creating ventricular pacing in vivo. The concept of this approach is novel in that an inherently short-lived gene delivery method using mRNA can deliver therapeutic modalities that require long-term function. The scientific premise for this idea is supported by our preliminary data that the transgene is an inherently short-lived protein, that ventricular-to-pacemaker cellular reprogramming occurs within the time window of the transgene expression, and that mRNA-based transgene expression creates de novo pacing in vitro and in vivo. The proposed project will translate this concept as a preclinical study by employing complexing synthetic mRNA with lipid nanoparticle (LNP) in a formulation that has already been approved and tested successfully in clinical trials. The objective is to evaluate clinical feasibility and safety of this approach with a goal to identify target clinical populations toward the first-in-human trial.