The study, appearing online today in Nature Medicine, is exciting for a number of reasons: Not only did the scientists modify a gene to correct the heart failure, they also developed a system that successfully delivered the gene to the heart and kept the gene active for seven months in more than 60 percent of the heart muscle cells, a very large percentage.
The results are a significant accomplishment in the field of gene therapy, which has been suffering since 18-year-old Jesse Gelsinger died in September 1999 after receiving gene therapy for a metabolic disorder at the University of Pennsylvania."I think this study is a very good example of what is potentially achievable. It's a very interesting, very important, very provocative proof-of-concept study," says Dr. P.K. Shah, director of cardiology and the atherosclerosis research center at Cedars-Sinai Medical Center in Los Angeles.
"But we cannot start doing this tomorrow in humans," adds Shah, who is conducting National Institute of Health-funded studies into the use of gene therapy for prevention of atherosclerosis, in which fatty materials build up along artery walls, eventually restricting blood flow.
The study authors agree the results, though dramatic, are early and any benefits to humans aren't imminent.
"It's sort of like the first Model-T. I'm not saying that this is a Porsche, but this will encourage a lot of other people to start thinking," says Dr. Kenneth Chien, senior author of the study and director of the university's Institute of Molecular Medicine.
Heart failure affects more than 4.5 million Americans. The disease has many causes and no cure outside of a heart transplant or mechanical pumping devices, both extreme measures.
"Any time we can have an impact, it's going to be a major medical advance," says Dr. Daniel Fisher, a clinical associate professor at New York University School of Medicine in New York City. "I'm excited about the potential impact, but I'm not hopeful that this is going to be clinically applicable any time in the foreseeable future."
The Nature Medicine study builds on a series of experiments dating back several years. The first milestone took place in 1997, when researchers produced mice with a genetic mutation that caused a defect in the heart's calcium pump. The defect resembled a similar defect in humans that is a major cause of heart failure.
Researchers then discovered that taking out a gene called phospholamban (PLN) completely prevented the onset of heart failure in mice with the defect. It seems humans with a defective PLN gene had the same problem. Inserting a modified PLN gene that counteracted the defective gene had the same effect as taking out the gene in the mice.
The next step was to test the results in a larger animal, one closer to humans. Enter the hamster, and the most recent set of experiments. Although the study was initially intended to see if the modified gene could prevent heart failure, the scientists got halfway through the experiment and realized they were actually stopping the progression of the disease.
The gene was initially delivered with an adenovirus -- or cold virus. But the results only lasted a week and included inflammation.
For this study, the researchers "borrowed" an adeno-associated virus that researchers at the University of Pennsylvania had used successfully in hemophiliac patients. The new virus, delivered by a catheter directly to the coronary arteries, did not produce inflammation of the heart and managed to halt heart failure for seven months. What's more, a single injection of the new virus worked well with heart muscle -- more than 60 percent of the ventricular muscle ended up "expressing" the gene.
"They demonstrate a very efficient transduction," says Dr. James Merritt, chief medical officer of Introgen Therapeutics in Houston. Transduction is the efficiency by which the modified gene is introduced into cells. "They give numbers around 60 percent, which is very high and the duration during which they were able to detect the gene itself was quite long and then, of course, they got some therapeutic activity."
Unfortunately, heart-healthy hamsters do not translate readily into heart-healthy humans.
"It's fantastic when you're talking about animals, but to think it's going to progress to human experiments any time soon is a pipe dream," Fisher says.
The procedure used to introduce the modified gene, though very efficient, was fairly violent, Merritt says. The animals had to be chilled to a low temperature to slow down the heart, and the heart vessels were temporarily blocked during the procedure. They also used a huge dose of the virus, Merritt says.
"There's no question that they did everything to the max to get the best possible results," Merritt says. And there's nothing wrong with that -- it just can't be repeated in humans.
In additional studies not mentioned in this paper, the researchers have shown that introducing the gene had a dramatic effect on halting heart failure progression in rats that have had heart attacks.
The catheter delivery system has been tried on 50 pigs and, Chien says, "if we keep progressing the way we are, we hope within 18 months or so we could begin the first clinical testing on [human patients] with severe heart failure and near end-stage heart failure."
"It will still be a risky procedure with its own set of problems, but it's biologically targeted. There's a rational reason for doing this. It's not just plumbing," Chien says.
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