SIGHTINGS


 
Breakthrough Gene Therapy
Making Old Hearts Young Again
3-8-99
 
BOSTON (AP) - "Genes," ordered the surgeon. Then he injected a syringe of pure DNA and salt water into a man's beating yellow-red heart.
 
Dr. James Symes stared for a moment into his patient's chest. The incision began just below the left nipple, ran through the lumpy layers of fat and muscle, then between the ribs, finally exposing the heart.
 
The surgeon moved the needle an inch. Again he slid it into the pulsing surface. And again. And again.
 
Ten minutes later, it was over. All that remained was for the patient to come out of anesthesia, heal up, return home to Monticello, Ark., and wait to see if his heart felt better. On this gray December morning, a 55-year-old logging contractor named Joe Griffith became Patient No. 20 in a groundbreaking medical experiment.
 
The goal: Give his heart some helpful new genetic material. If it worked as planned, these test-tube genes would prompt the growth of tiny blood vessels in just the right spots, shuttling blood around places where the coronary arteries were painfully clogged. Griffith would quite literally grow his own bypass.
 
Griffith's surgeon at St. Elizabeth's Medical Center had injected his heart with several billion identical copies of the gene. Each carries the manufacturing instructions for a protein known as vascular endothelial growth factor. Ordinarily humans make this stuff only while in the womb, when it triggers the construction of their circulatory system.
 
On this day, no one could say with certainty what these genes would do for Griffith. Might they, as he hoped, ease his chest pain? Restore his stamina? Just driving into the woods to check on logging crews left Griffith exhausted. Even a little relief would be welcome.
 
The experience of the previous 19 patients at St. Elizabeth's encouraged him.
 
There was, for instance, the very first one in the experiment, a 67-year-old man treated in February 1998. He needed eight nitroglycerin tablets a day for angina that came on with the slightest activity. All of his natural coronary arteries were plugged. So were three of the four new ones stitched in during earlier bypass surgery.
 
Three weeks after the gene injection, his angina began to ease. Two months after the operation, the pain was gone. He gave up nitroglycerin and took up swimming.
 
Then there was the second patient, a 69-year-old man who'd get angina after walking 10 yards. Three weeks after the operation, nothing had changed. Then his pain gradually let up. By two months, he was going to the gym and riding an exercise bike for a half hour at a stretch.
 
Animal tests suggest that the genes become lodged inside heart muscle cells, which then secrete growth hormone for a week or two. This prompts the growth of what doctors call collaterals, tiny blood vessels thicker than a hair but thinner than the skinniest strand of pasta.
 
"It has surprised a lot of people in the gene therapy field to see that it's possible to achieve these effects with something as simple and nontoxic as naked DNA,'' says Dr. Jeffrey Isner, who oversees the experiment at St. Elizabeth's.
 
That's not all that surprises them. Perhaps most astonishing is the fact that the infant field of gene therapy has taken this turn at all, that it shows its first clear promise against heart disease, the biggest killer of mankind.
 
For the last decade, it seems, gene therapy has been perpetually on the horizon, tantalizingly close but never drawing nearer.
 
Those who championed the approach long predicted it would be used first to cure rare inherited diseases, such as cystic fibrosis. They occur because the body lacks a single critical protein, the result of garbled genes that fail to lay out proper manufacturing instructions.
 
The idea of gene therapy is to make good copies of the bad genes and insert them into the body. There they will oversee construction of the missing protein, curing the disease. Or so scientists hoped.
 
They were heartened at first to find they actually could put the new genes into cells and get them to work. But the benefits didn't last. The genes petered out after a few weeks, ending production of the protein that the body needs in steady supply for a lifetime to reverse inherited illnesses.
 
Pioneers of the field, like Dr. Ronald G. Crystal of New York Hospital-Cornell Medical Center, finally acknowledged that the know-how was not good enough " at least, not yet " to install replacement genes that would carry on forever.
 
"So we began to think: What are the applications where you only need to change the genetic information for a week or two?'' Crystal says. "That led to the concept of building new blood vessels.''
 
Proteins like vascular endothelial growth factor, or VEG-F, are triggers. They set off a chain reaction of protein release that eventually ends in blood vessel growth. Once the process is under way, there's no need for more VEG-F.
 
Isner, Crystal and others first showed the power of this protein in animals, then in people with clogged leg arteries and finally in the human heart.
 
Most of the patients have been as bad off as Griffith, a genial, low-key man with awful chest pain and no alternatives. He had his first coronary bypass operation at age 37. Over the years, his arteries were reamed with routers and squeezed with angioplasty balloons. Still, two of his coronary arteries were totally blocked. So, too, were two veins that had been stitched in during bypass surgery.
 
Last April, a third bypass vessel closed off. The chest pain got so bad that Griffith could barely walk 100 yards without a rest. Ordinary medicine and surgery offered nothing more for him.
 
The afternoon before his gene operation, Griffith sat in pajamas on his hospital bed and told how the worsening angina had left him barely able to run his logging business:
 
"I leave home early for the office, get the crews going, go home to rest, get in my pickup, go to the job, stay a couple of hours, go home and take a nap, go to the office for a little while than then go home, exhausted.''
 
Griffith hoped for the best. "I'd be pleased with any help at all,'' he said that day. He knew the statistics seemed to be in his favor.
 
The first 18 patients in the program all reported that their angina had improved. Of the 11 followed for more than three months, six were free of pain entirely. Their average nitroglycerin use had fallen from 60 pills a week to 2 1/2.
 
Tests, too, suggested they were doing better. X-ray movies called angiograms showed improved blood flow. And radioactive thallium scans revealed a one-third increase in the amount of heart muscle getting adequate oxygen.
 
"If it works, and that's a big if, this could play a major role in treating heart disease,'' says Crystal, who's team has performed gene therapy on 21 heart patients. "What we are trying to do is make the old heart young.''
 
One obvious benefit could be for the 250,000 Americans whose lives, like Griffith's, are disrupted by chest pain, even though they have already had angioplasty or bypass surgery and take all the standard medicines.
 
An obvious drawback is the mini-thoracotomy, the operation Griffith had. Isner and Crystal believe the genes must be injected directly in the heart muscle to work. Thus the need to cut open the chest.
 
One way around this would be to thread a catheter into the heart with a needle on the end of it. The approach seems to work in animals, but it is not yet ready for people.
 
However, releasing fluids into the heart through catheters is already routine. Some doctors say injecting the genes with needles is unnecessary. Just putting some genes into the heart's circulation should be enough. A group led by Dr. H. Kirk Hammond of the Veterans Administration Hospital in San Diego recently started such experiments.
 
"One of the things we find very exciting is the possibility that patients may never need to see the inside of an operating room and still have their coronary artery disease attended to in a very thorough way,'' says Hammond.
 
In fact, his study will involve about 100 patients with ordinary treatable angina, not the worst-case patients of Isner and Crystal.
 
While cardiologists and surgeons are intrigued by these experiments, many seem cautious, even dubious, about the prospects.
 
Some believe that genes are not needed at all. Squirting pure VEG-F into the heart might do just as well, even though the protein lasts only 10 minutes or so. Studies of this approach are also under way.
 
Some wonder if gene therapy has moved too fast from lab animals to humans without enough evidence that the newly created blood vessels will hold up over the long haul.
 
"My personal view is that this has rushed pretty quickly to the clinic, probably before we have understood it to the degree that would satisfy me,'' says Dr. R. Sanders Williams, chief of cardiology at the University of Texas Southwestern Medical Center.
 
Others caution that too much is being made of small, preliminary studies in a handful of patients.
 
"It's tremendously promising, but it's not ready for prime time,'' says Dr. Robert Roberts of Baylor University. "There are lots of wonderful anecdotal stories in one patient. That's not science.''
 
One of the most often repeated concerns is that the patients' improvement, amazing as it seems, is merely what scientists call a placebo effect: Patients have holes cut in their chests. They dearly want to feel better. And they do. The benefit is all in their heads.
 
"It's hard to believe how someone could imagine themselves into a better thallium scan,'' counters Isner.
 
Someone else is pretty sure this is no placebo effect: Griffith. One Monday five weeks after the operation, he woke up feeling better. Now two months have gone by, and he's back to work full time, managing crews from 5 a.m. to dark. He still has some chest pain, but nothing like before.
 
"I used to do most of my work from the seat of my pickup, but it reached the point where I couldn't do that,'' he says in his quiet way. "I was unable to do just about anything. Now I can get around without wearing myself out. I think I'm coming around.''





SIGHTINGS HOMEPAGE