Preclinical development of biological pacemakers

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Abstract: Chronic right ventricular (RV) pacing can cause RV pacing-induced cardiomyopathy (RPVIC). Approximately 20% of patients paced from the RV apex develop RVPIC, with a dramatic depression of systolic function. Symptomatic heart failure is not infrequent, and long-term outcomes are poor. Clearly, alternatives to RV pacing are desirable, but there are no validated preclinical models of RVPIC to help understand mechanisms and to guide therapy. Here we seek to validate a non-tachycardic pacing model of RVPIC in a porcine model of complete heart block, and to use this model to test biological pacemakers (BioP). Gene-based BioP were first described more than a decade ago; somatic gene transfer of various constructs (a dominant-negative mutant of the inward rectifier channel [Kir2.1AAA], wild-type HCN channels, and a transcription factor [Tbx18]) have all been shown to create BioP activity. However, until recently, in vivo preclinical applications have been mostly limited to highly-invasive open-chest models. We have developed a clinically-realistic minimally-invasive delivery technique and used it to create BioP in a porcine model of complete heart block. Here, we propose to use this approach to compare two “finalist” therapeutic candidates with fundamentally different mechanisms of action. The first one is a wild-type ion channel (HCN2) that artificially induces automaticity in ventricular cardiomyocytes by functional re-engineering. The goal is not to create a faithful replica of a pacemaker cell, but rather to manipulate a single component of the membrane channel repertoire so as to induce spontaneous firing in an excitable but normally-quiescent cell. The active principle of the second therapeutic candidate, Tbx18, reprograms ventricular cardiomyocytes into sinoatrial node (SAN)-like pacemaker cells (induced SAN [iSAN] cells). No one determinant of excitability is selectively over-expressed: the entire gene expression program is altered, with resultant changes in fundamental cell physiology and morphology. This proposal utilizes the above mentioned percutaneous delivery method to reduce to refine and validate, in a large-animal model of RVPIC, the approaches required for translation to the clinic. We will characterize and compare the pacing efficacy and safety of HCN2 and Tbx18-derived BioP, testing the hypothesis that iSAN cells will provide superior chronotropic support as compared to HCN2. Once designating the most promising therapeutic candidate, we will then test the utility of BioP in the setting of RVPIC. We hypothesize that restoring antegrade conduction by his-bundle pacing with a BioP can attenuate or reverse the adverse ventricular remodeling associated with right ventricular pacing. This research proposal is designed to lay the pre-clinical groundwork for testing of an optimized BioP in patients at risk for RVPIC.