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Year after year, heart disease is the number one killer in America. In researching a treatment, scientists have poured resources into developing potential heart replacements. But the key to solving the epidemic may not be finding an alternative heart, but repairing the original.
To that end, Gladstone Institutes may have an answer. Researchers have found a way to genetically reprogram scar tissue in the heart to make it behave like muscle tissue. By introducing a cocktail of genes into scar-forming heart tissue after a heart attack—before the tissue has a chance to scar—they can transform the damaged cells into beating cells, which can strengthen the heart as a whole.
“We're trying to avoid a heart transplant,” said Dr. Deepak Srivastava, Gladstone's Cardiovascular and Stem Cell Research Director.
In a recent study, published in the latest issue of the journal Stem Cell Reports, scientists injected five genes into human scar-forming heart tissue, known as fibroblasts, and found that 20 percent of the cells were capable of transmitting an electrical signal. Srivastava said those rates could be even higher if the fibroblasts are transformed in vivo, rather than in a petri dish. In an experiment with mice last year, scientists found that 50 percent of fibroblasts were able to carry a pulse.
If the genetic cocktail is approved, here’s how it would work in a practical scenario. After a heart attack, heart cells in the affected area die and become shrouded in scar tissue. A stint, impregnated with chemicals, is placed into a patient’s heart. Doctors have a window of several days to two weeks to convert those scar-forming cells into muscles.
The stint slowly releases its contents over a three-week period. “Cells start reprogramming within three days and then over the next four to six weeks they get more mature,” said Srivastava. The team is also exploring other methods for treatment delivery and procedure, and is gearing up to experiment with pluripotent cells in tandem with the gene therapy treatment.
That’s where there might be hope for patients with chronic heart disease. Once a scar has formed it can’t be altered, but Srivastava thinks that by creating new muscle that’s able to pump in synchrony with the existing muscle, he’ll be able to strengthen hearts weakened by disease.
Five million people suffer from heart failure every year. “My father is one of them," said Srivastava. "He's 76, and has had quite a few heart attacks... There aren't too many options.” Most people who suffer a heart attack never fully recover. They struggle to climb stairs—even walking becomes a perilous task. The waitlist for a heart transplant is epically long, and while xenotransplantation has advanced in recent years, it’ll be a long time before pig heart transplants become a regular procedure at hospitals.
Right now, stem cell researchers are on the forefront of creating organs, bones, and muscles from scratch. Though still in the early stages, some success has been reached using pluripotent cells––stem cells manually created from normal cells. So far, scientists have been able to turn pluripotent cells into pulsating cardiovascular cells. An article published earlier this month in the journal Nature reported that scientists at the University of Pittsburgh had successfully decellurized a rat heart of its rat cells, and repopulated it with pluripotent human cells, resulting in a tiny, beating, human-celled heart.
Now, they’re working on replicating the experiment with a pig heart in the hopes it could be used as a transplant. Srivastava said his lab is also working with pluripotent cells, and that there’s a lot of potential for advancement in that arena.
Still, there are a lot of hurdles. One is a matter of environment. Though scientists are able to generate a large numbers of heart cells in a petri dish, they have difficulty transplanting them in an organ. “We've had trouble getting those cells to mature to an adult state. We've also had difficulty getting them to connect to the existing heart cells in the organ,” said Srivastava.
Another issue is that when stem cells are introduced into a body, they can always go rogue—despite scientists' best efforts to coax them to perform a particular function. The biggest concern is that they’ll turn into cancerous cells, but really, they can become anything.
The benefit of Srivastava’s gene therapy is that no extra stem cells are produced. He’s reprogramming scar tissue cells that are already present in the heart. “When those cells do mature, they turn out more adult-like and they integrate quite well with their neighbors and can contribute to the pump function,” he said.
As of right now, the lab is studying the effect of gene therapy on pig hearts, though a conclusion is still two years out. Srivastava says it will be at least five years before gene therapy becomes a viable treatment. In the meantime, heart disease patients will have to make due with dietary restrictions, exercise, and pre-emptive nanotechnology.