While electronic pacemakers have successfully been used for more than 50 years and continue to undergo refinement, they remain associated with complications and limitations, including battery life, system failure, inability to provide true autonomic response, and device-related infections that can be life-threatening. Electronic pacemakers are particularly traumatic and risky for pediatric patients, as they must be regularly refitted as children grow.

After two decades of intensive study, researchers in the Smidt Heart Institute at Cedars-Sinai are getting closer to an alternative: biological pacemakers using somatic reprogramming strategies. This approach would involve the transfer of genes encoding transcription factors to transform working myocardium into a surrogate sinoatrial node.

Using gene therapy to treat atrioventricular block
A team led by Eugenio Cingolani, MD, and Eduardo Marbán, MD, PhD, launched a project to explore a biological pacemaker that would harness the power of gene therapy to treat heart block in animal models. The researchers injected pigs with a gene called TBX18—which is active during embryonic development but then switches off—delivering it to the heart.

Results published in Science Translational Medicine indicated that TBX18 had successfully sped up heart rates that had been slowed by heart block in the pigs, reprogramming normal ventricular cardiomyocytes into induced sinoatrial node cells. The team subsequently received a grant of $3 million from the National Institutes of Health (NIH) to pursue their research on next-generation pacemakers.

A departure from previous technology
Prior to the work done by Cingolani and Marbán, most approaches to biological pacemakers relied on overexpressing ion channels to create abnormal automaticity in working myocytes. Proof of concept was primarily at the cellular and small-animal levels, with few follow-up translational studies.

Twenty years ago, when the idea of a biological pacemaker was still in its infancy, Marbán—who is currently the Executive Director of the Smidt Heart Institute at Cedars-Sinai and the Mark Siegel Family Foundation Distinguished Professor—and his colleagues had published the first successful gene-therapeutic approach toward the generation of pacemaking activity in otherwise nonpacemaking adult cardiomyocytes using a guinea pig model.

In a collaboration between the NIH-funded Cingolani Lab and the Marbán Lab in the Smidt Heart Institute, Cingolani and Marbán not only were able to create a biological pacemaker by expression of a specific gene (TBX18) but also used a novel approach: They delivered it using a minimally invasive delivery (catheter-based) system, thus avoiding the need for a major surgical procedure.

Another potential breakthrough: Harnessing mRNA
Most recently, Cingolani—who directs Cedars-Sinai’s Cardiogenetics-Familial Arrhythmia Clinic—and his colleagues published the results of their research on a new strategy for introducing TBX18 into an organism. Implementing a technology similar to the one used in the Pfizer-BioNTech and Moderna COVID-19 vaccines, the scientists tested the use of mRNA as an alternative to viral-vector strategies for delivering TBX18.

Direct delivery of mRNA may be an attractive alternative due to the inherent limitations and potential risks of viral-mediated gene delivery, including systemic side effects. In research published in Cell Reports Medicine in December 2022, the authors explained that they used stabilized mRNA, which involved making nucleoside modifications in order to address nonmodified mRNA’s susceptibility to cleavage by RNase and rapid immune clearance when delivered in vivo. They reported that transfections of mRNA induced rapid transgene expression with no risk of insertional mutagenesis.

Objectives and next steps
The research suggests that an mRNA-based strategy is a viable avenue for further investigation, including studying ways to enhance its efficacy and efficiency. However, the mRNA-based approach has yet to be directly compared to viral vector-mediated strategies in terms of safety and efficacy. In addition, potential off-target effects have not been fully characterized. At this stage, the team’s viral-vector strategy is closer to being translated to humans—Cingolani believes testing in human subjects could begin within the next five years.

When that time comes, the goal is to first help patients who need their pacemakers temporarily removed to treat a pacemaker-related infection, given the complexities involved. As progress continues, biological pacemakers could become an important option, or one day even eschew the need for electronic devices altogether.

For more on biological pacemaker research, contact Eugenio Cingolani, MD.