Using a minimally invasive gene delivery method, researchers at the Cedars-Sinai Heart Institute have managed to directly reprogram regular heart muscle cells into cells of the heart's main pacemaker, the sinoatrial node, in pigs.

The cellular pacemaker "suffices to support the demands of daily life," corresponding author Eduardo Marban told reporters at a press conference announcing his team's results.

The cells also responded to exercise by speeding up the heart rate, and slowing it back down afterward – responses "which were absent in control pigs that had been treated only with an electronic pacemaker," he said.

In their experiments, which were published in the July 17, 2014, issue of Science Translational Medicine, the authors used a catheter to deliver a viral vector containing the transcription factor TBX-18 to a part of the heart that normally does not control the rhythm of heartbeats, but follows the signals generated by the sinoatrial node instead.

Animals with an experimentally induced form of complete heart block, which blocks the sinoatrial node from initiating heartbeats, developed a new cluster of pacemaker cells that generated a heartbeat when they were treated with TBX-18. "The newly created node then takes over as the functional pacemaker bypassing the need for implanted electronics and hardware," Marban said.

The work "heralds a new area of gene therapy where genes are used not only to correct a deficiency disorder, but actually to convert one type of cell into another to treat disease," he said.

In their experiments, the authors used a form of reprogramming that is related to the generation of induced pluripotent stem (iPS) cells, but goes directly from one somatic cell type to another without an intermediate embryonic stem cell-like state.

Marban said the basic principle of directly converting one cell type into a related cell type in the body is one that might ultimately find multiple applications. Other research groups are working to see whether the delivery of different genes can generate sound-sensing hair cells in the inner ear and pancreatic islet cells, to treat deafness and diabetes, respectively.

For the time being, "our work is the first to harness the therapeutic power of somatic reprogramming in a life-threatening disease using a realistic large animal model," Marban said. "To date, such approaches have worked well in the dish and in small animals, but somatic reprogramming has not previously been used in a large animal model to correct a disease using clinically realistic methods, nor has it been used to treat any life-threatening illness."

According to Thomson Reuters' Incidence & Prevalence Database, 370,000 pacemakers were implanted in the U.S. in 2010. Ultimately, biological pacemakers could conceivably replace many of those devices.

The team hopes to be in clinical trials with their approach within about three years, and initially plans to focus on two groups of patients that could benefit from biological pacemakers, co-author Eugenio Cingolani told reporters.

"The first are fetuses with congenital heart block," he said. "Such babies still in the womb cannot have a pacemaker implanted and they develop severe heart failure often resulting in stillbirth. We hope to work with fetal medicine specialists to create a life-saving biological pacemaker in fetuses that have been identified to have congenital heart block."

Another group that needs an alternative to pacemaker devices is adults whose pacemakers need to be removed due to an infection.

Drug-resistant biofilm infections on medical devices are an already large and still increasing problem, and in extreme cases, the device needs to be removed until antibiotics eradicate the offending bugs. Currently, patients live without a pacemaker for the two to six week duration of such antibiotic treatment if they can, and receive an interim device if they must. But neither approach is ideal.

If direct reprogramming of heart muscle cells proves successful in those patient groups, Cingolani said, "the technique could eventually become a realistic alternative to regular pacemaker in a broader spectrum of patients. Rather than having to undergo implantation of a metallic device that needs to be replaced periodically and can fail or become infected, patients may someday be able to undergo a single gene injection and be cured of the slow heart rate forever."

"If you look at the natural history of other first in class treatments for heart rhythm disorders, they start with the most arcane and difficult cases," Marban said. But "ultimately they become generalized to be able to treat hundreds of thousands of patients. And we wouldn't be surprised if that's the path that this takes."