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Published: Wednesday, 7/16/2014 - Updated: 3 months ago

Gene therapy used to create ‘Biological Pacemaker’ in pigs

NEW YORK TIMES

By injecting a gene into a pig’s heart, scientists have created a “biological pacemaker” that can regulate heartbeats, an achievement that eventually may lead to an alternative to electronic pacemakers in some people.

The technique also may prove to be a promising example of gene therapy, which so far has shown glimmers of success in just a few other conditions.

Researchers at the Cedars-Sinai Heart Institute in Los Angeles reported today that they had injected a gene into a tiny section of pigs’ hearts and were able to temporarily reprogram ordinary heart cells into rhythm-generating cells. Human trials of the technique are at least three years away, and if successful, the approach would be, at least at first, limited to a small subset of pacemaker users.

Dr. Eduardo Marbán, director of the heart institute and one of the authors of the study, which appeared in Science Translational Medicine, said the work was the first in which this genetic approach, called “somatic reprogramming,” had been used to address a life-threatening condition in a large animal. Pig hearts are similar to human hearts in many ways.

In the heart, a small area of cells, called the sino-atrial node, acts like a metronome, setting the pace of its beat. Certain conditions cause the heart to beat too slowly or with a dangerously irregular rhythm.

Electronic pacemakers correct that problem for some 300,000 people a year, but a small number of heart patients cannot use them safely. About 2 percent of pacemaker users develop infections that require the device to be removed while the infection is treated, Marbán said. Some require a temporary pacemaker until the infection clears.

The 12 pigs in the study had a condition called “complete heart block,” in which the sino-atrial node gets disconnected from the main pumping chambers of the heart, causing a very slow heart rate.

Marbán said there are only several thousand sino-atrial node cells in the heart, while billions of ordinary heart cells act to spread the pulse that allows the heart muscle to pump blood throughout the body. The researchers noticed that a gene called TBX-18 is activated briefly in the sino-atrial node of developing embryos, suggesting that it may play a role in creating rhythm-generating cells. So the researchers decided to try injecting TBX-18 into pigs’ hearts.

Half of the pigs were injected with the gene, while the others were given an inactive green protein to monitor the activity of their hearts and a backup electronic pacemaker if they needed it.

In pigs given the gene, heart rates quickened as they would with electronic pacemakers. Heart rates also responded to the pigs’ physical activity, accelerating when the pigs exercised, slowing when they rested, Marbán said.

The effect lasted only two weeks, and began tapering off around 11 days, but the researchers are continuing experiments to see if the effect can last longer. For now, even if the approach ends up being successful in humans, it would be useful only in situations in which implanted pacemakers must be removed because of infection or in the rare cases of fetuses experiencing complete heart block in utero, said another study author, Dr. Eugenio Cingolani.

Still, experts not involved in the study said the work represented a significant step.

Dr. Ira Cohen, director of the Institute for Molecular Cardiology at Stony Brook, who has worked on other approaches to biological pacemakers, called the new research “remarkably clever” because Marbán “picked a specific problem and did it in a very specific way.”

“Other people have tried it — he made it work,” Cohen said.

“It is very disappointing how much the efforts in gene therapy and cell therapy have yielded, so this little advance gives the hope that using a creative gene therapy approach can work,” he added.



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