CDU

Cardiologists in the U.S. put in close to 300,000 electronic pacemakers annually. And the 10-year expense for a patient with a pacemaker, including annual checkups and battery changes, may average $30,000 to $40,000.Those facts of cardiac life impelled molecular biologist Eduardo Marban of Johns Hopkins University School of Medicine (Baltimore, Maryland) to "pursue ideas of going in with a catheter percutaneously and injecting one very small part of the heart non-invasively under X-ray, and creating a natural pacemaker." He foresees the patient walking away and never needing a battery change or hardware implanted."

Marban is senior author of a Brief Communication in the Sept. 12 issue of Nature, titled, "Biological pacemaker created by gene transfer."

"We've been able to create this," he told CDU's sister publication, BioWorld Today, "by converting normally quiescent muscle cells in the heart into pacemaker cells. We see this as a potential alternative to electronic pacemakers." It's the first instance, Marban said, "in which gene therapy has been used to alter the function of an organ, or a bit of an organ."

He said the potential applications "are limited only by one's imagination. With 30,000 human genes available to use, we have all the applications we can imagine. Anything in which there's some kind of deficiency or error in the body could in principle be fixed or repaired using this method."

Marban said, "It's analogous to taking a very clunky car and, if you had access to all of the good mechanics in the world, plus all of the components in parts warehouses, you could transform that lackluster jalopy into a hot rod."

What Marban reported is "selectively suppressing one particular gene in the heart and thereby changing a garden-variety cardiac cell into a pacemaker that beats its own rhythm.

"We started off facing the challenge of how to fashion a biological pacemaker, using gene therapy. We realized that if we go back to when the embryo is very young and its heart is just forming, it would be in an incipient human at two or three weeks of age." Every cell in the heart at that point, he said, "has intrinsic pacemaker activity, so can set the rhythm. But very quickly thereafter, another couple of weeks in the embryo, the heart differentiates into very discrete regions, only one of which can normally pace. And that sets the rhythm for the heart for the rest of one's life – until disease or some kind of degeneration associated with aging leads to failure of the normal pacemaker mechanism."

What happens in that heart as it becomes more and more adult, Marban said, "is that only a few thousand cells possess this intrinsic pacemaker activity. The rest of them are mostly muscle cells, there to beat – to do the job of the heart." That's nice, he said, "because then some of the cells can focus on beating, and others on pacing. If a few thousand of those pacemaker cells get sick or if scar tissue forms around them, the heart develops standstill. That's when people will faint, and that's when electronic pacemakers are put in."

Using the fact that the embryonic heart possesses the intrinsic ability for every individual cell to beat, he said, "we thought, 'What if the cardiac muscle cells lose their ability to beat spontaneously because they develop an electrical braking mechanism?' So we identified a specific potassium channel that we thought was that braking mechanism. It had precisely the right characteristics to stop the heart and keep it quiescent. So we engineered a gene-transfer construct designed specifically to block that electrical brake. And, lo and behold, it liberated rhythmic spontaneous pacemaker activity."

He said the researchers put the gene into the ventricle "and converted a few of those ventricular muscle cells into pacemaker cells. In some instances, that sufficed to take over and drive the heart and initiate the heartbeat. We then created a poison-pill genetic construct. It's a mutant version of the gene that is normally expressed, which forms this potassium channel. Thus, we were able to cripple the body's own normal products of that gene in those cells where it was expressed."

For their in vivo experiments, the co-authors rounded up 25 guinea pigs, some dedicated to testing electrophysiology, others to electrocardiograms. "In about 70% of the cells that we studied, we were able to induce pacemaker activity from a normally quiescent ventricular myocyte, and turn those into spontaneously beating biological pacemakers," Marban said. "What's more, in 40% of the animals, we saw evidence that their hearts were driven by these pacemakers that we created in the ventricle."

In a human, he said, "we would go in with a catheter and locally convert a few thousand cells into pacemaker cells." For safety, efficacy and durability studies, Marban added, "we are now doing experiments in full-grown pigs, using clinically available catheters and X-ray equipment, with a view to establish preclinical groundwork for eventual Phase I human studies three to four years from now – if all goes well."