# Biological pacemaker from proof-of-concept to clinic

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $852,020

## Abstract

Project Summary
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.

## Key facts

- **NIH application ID:** 9838279
- **Project number:** 5R01HL135866-04
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Eugenio Cingolani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $852,020
- **Award type:** 5
- **Project period:** 2016-12-27 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838279

## Citation

> US National Institutes of Health, RePORTER application 9838279, Biological pacemaker from proof-of-concept to clinic (5R01HL135866-04). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/9838279. Licensed CC0.

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