The overall objective of the proposal is to lay the preclinical groundwork for first-in-human studies of biological pacemakers (BioP) as alternatives to electronic devices. 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 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. The proposal utilizes the abovementioned percutaneous delivery method to refine and validate, in a large-animal model of bradycardia, 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. We will go on to perform long-term efficacy, toxicology and biodistribution studies with the more promising therapeutic candidate, and then prepare, and obtain approval of, an Investigational New Drug (IND) application for a first-in-human BioP trial. While the ultimate goal may be to render obsolete the electronic pacemaker, it is important to be realistic in thinking about potential first-in-human applications. Therefore, we have chosen to develop, initially, a bridge-to-device product that will temporarily provide hardware-free chronotropic support in infected patients who are pacemaker-dependent. To make BioP temporary, we deliver the genes in adenoviral vectors, relying on immunological clearance to limit bioactivity. Nevertheless, we will test catheter ablation of the BioP as a backup rescue strategy in case of persistent undesired BioP activity. This research proposal is designed to lay the groundwork for clinical testing of an optimized BioP initially in a needy population.
Abnormally slow heart rhythms affect many people in the USA, and those numbers are steadily increasing as the population ages. While electronic pacemakers are the mainstay of therapy for these conditions, complications from device implantation, such as life-threatening infections, may occur. As an alternative to electronic devices, we propose to study select biological pacemaker candidates in a pre-clinical model of complete heart block, and to develop the most promising candidate as a potential therapeutic agent for first-in- human application.
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|Cingolani, Eugenio; Goldhaber, Joshua I; Marbán, Eduardo (2018) Next-generation pacemakers: from small devices to biological pacemakers. Nat Rev Cardiol 15:139-150|
|Cho, Jae Hyung; Zhang, Rui; Kilfoil, Peter J et al. (2017) Delayed Repolarization Underlies Ventricular Arrhythmias in Rats With Heart Failure and Preserved Ejection Fraction. Circulation 136:2037-2050|