Gene Therapy for the Heart: Biological Pacemakers Work Without Surgery, Batteries or Wires
U.S. researchers have successfully used gene therapy to turn regular human heart cells into pacemaker cells. This opens the door to the possibility of life-saving pacemakers without surgery, wires or batteries.
"This is the culmination of 10 years of work in our laboratory to build a biological pacemaker as an alternative to electronic pacing devices," said Eduardo Marbán, Ph.D., director of the Cedars-Sinai Heart Institute in Los Angeles and co-author of a recent Nature Biotechnology article on the research.
In 2002, Marbán developed an early biological pacemaker by suppressing a gene. This began a decade-long search for a gene therapy to make a biological pacemaker indistinguishable from natural pacemaker cells.
Thousands of pacemaker cells deliver an electric signal that drives the beat of every heart. Cardiac rhythm disorders reflect failures in the generation and conduction of this signal. Traditional pacemakers treat the symptom of an irregular heartbeat but not the underlying condition. Still, about 200,000 Americans have received pacemaker implants each year.
Principal Investigator Dr. Hee Cheol Cho and his team modified the DNA of regular heart cells to match pacemaker cells using a technique called cell reprogramming, which involves inserting foreign elements called transcription factors into cells. The entire genome is in every cell, but unless a transcription factor turns on a particular gene, that gene will be inactive. A cell’s type and what it does is determined by the activated genes within it.
“It's a gene switch,” Cho said. “Some transcription factors turn the gene on, others turn it off.”
Cho and his team found that, to reprogram a regular heart cell into a pacemaker cell, they only needed to express one transcription factor, called Tbx18. They added the gene that expresses Tbx18 to the genome using adenoviruses, which penetrate the cell’s nucleus and modify its DNA.
Tbx18 was about the fifth transcription factor Cho and his lab tested. It was selected because a 2009 study indicated it played a significant role in embryonic heart development. Cho hoped that role would be in making pacemaker cells.
Dr. Cho injected the the Tbx18-augmented adenovirus into human heart cells cultured in petri dishes. Two days later, the reprogrammed cells started to pulsate.
"Just like a human heartbeat," he said.
A week after being injected with the adenovirus, the cells shifted from being rectangular, like typical heart cells, to irregularly shaped, like pacemaker cells. Muscle fibers became weak – a good sign – because the pacemaker’s job is "not to pump blood, but to generate an electrical signal,” Cho explained.
Next, they injected the adenovirus directly into guinea pig hearts, while researchers at Weill Cornell Medical College developed a similar gene therapy approach that reprograms scarred heart tissue into healthy tissue. Todd Rosengart and his lab expressed three transcription factors that induced changes to make the cells healthy again.
"Now we need to go further to understand the activity of these genes and determine if they are effective in even larger hearts,” he said.
Like large animals. Cho’s team is moving on to test the biological pacemaker in pigs, while Rosengart’s will run more trials with rats first. “We envision three to five years of pre-clinical, large animal testing.”
Then, Cho said, they’ll begin designing human trials.
“So far the data is extremely encouraging, but we take it one step at a time,” Rosengart said.
They determined the beat was triggered by two mechanisms, which were present in both the natural and reprogrammed pacemaker cells. Current trials are aimed toward determining whether the reprogrammed pacemaker is totally indistinguishable or practically indistinguishable from its natural counterpart.This year, Rosengart hopes to begin a trial on a gene therapy to grow new blood vessels, which he says are on the rise. His outlook is positive.
“Although I can’t prove it, I am fairly certain that the next five years will witness cures for genetic diseases, the regeneration of healthy new organs from diseased ones, and even exciting new (gene therapy) treatments for cancer,” Cho wrote in an editorial on a blog on the Houston Chronicle, “I know, you’ve heard it before, but I really believe this time is different.”