"The pace of progress in the field of cystic fibrosis has been absolutely staggering," said James M. Wilson, who will head the project at Penn. "I am very hopeful that the procedures we use will eventually lead to a cure for cystic fibrosis."
But that's not all. While cystic fibrosis could be the first major disease to be conquered by gene therapy, it almost surely won't be the last.
Nine different gene-therapy experiments are already going on at medical centers in the United States, and several more are being planned in the Netherlands, China and Italy. Various techniques are being tried for kidney and skin cancer and the buildup of high levels of cholesterol in the body. Other experiments are being planned for other illnesses, including AIDS, ovarian cancer, lung cancer and brain cancer.
Taken together, these efforts amount to a true revolution in medicine.
The first gene therapy was done in September 1990 on a 4-year-old Texas girl who suffered from a rare immune-system disease known as ADA deficiency. She is now healthy enough to go to school and risk exposure to common childhood diseases.
Since then, the field of gene therapy has moved more rapidly than even its most fervent proponents had hoped.
"Gene therapy will be as important to 21st-century medicine as vaccines and antibiotics have been to the 20th," said William Kelley, chief executive officer and dean of the University of Pennsylvania Medical Center, which will oversee Wilson's experiments. "Many of the most important breakthroughs in medicine will occur in the area of human gene therapy - revolutionizing medicine as we know it today."
In its simplest form, gene therapy involves inserting healthy genes into a patient's cells to compensate for a hereditary deficiency.
Every human being has about 100,000 genes - packets of biochemical information that tell the body how to develop and function. Slight errors in these chemical instructions can make the body's processes go awry. An estimated 4,000 diseases - including cancer and heart disease - are believed to be either caused or affected to some degree by faulty genes.
Gene therapy is not risk-free. Some scientists fear that attempts to fix one genetic defect could trigger other serious medical problems - cancer, for instance. And even if gene therapy proves safe and effective, researchers say, the treatment could be so costly that only the very rich or very well insured could afford it.
Still, Kelley, who arrived at Penn in 1989, is staking his reputation and much of the future of his institution on gene therapy.
When Wilson, a University of Michigan geneticist, comes to work for Kelley in March, he will direct Penn's new Institute for Human Gene Therapy. Wilson's gene research will be central to the new institute.
Kelley expects the institute to draw on the scientific expertise in genetics, virology and other medical disciplines not only at Penn but also at the Wistar Institute, Children's Hospital of Philadelphia and area companies.
A number of gene-therapy labs will be built at Wistar, located on the Penn campus, and in two new biomedical research buildings that are planned.
By the end of the decade, Kelley predicts, between 150 and 200 people, including 25 senior scientists, will be working at the new institute.
Wilson and his team of about 15 gene-therapy specialists will work not only on cystic fibrosis but also on a fatal cholesterol disorder known as familial hypercholesterolemia.
In June, Wilson inserted new genes into the body of a 29-year-old Quebec woman with this disease. He reported this month that the treatment had reduced the woman's cholesterol by 20 percent to 40 percent, and that she was faring well. The federal government gave him permission to treat four more patients.
Penn is not the only Philadelphia institution involved in gene-therapy research. Scientists at Thomas Jefferson University are involved in experiments that could lead to gene therapies for leukemia, bladder and skin cancer, and skin diseases. None of those experiments is ready yet to be tried on humans.
At Penn, the cystic fibrosis experiments are expected to get underway in the spring.
About 30,000 Americans suffer from CF, a disease that clogs the lungs with thick mucus, eventually destroying lung tissue. Current treatments merely slow the disease's inevitable progression, and more than half of CF patients die by their late 20s.
Three gene-therapy experiments for CF - Wilson's at Penn, another at the National Institutes of Health and a third at the University of Iowa's Howard Hughes Medical Institute - were approved Dec. 3 and 4 by the Recombinant DNA Advisory Committee, a federal panel that oversees gene-therapy research.
Before they begin, the experiments must be approved by the federal Food and
Drug Administration and the director of the National Institutes of Health, but researchers expect no opposition there.
In the last few years, as scientists have begun to pinpoint the precise genes responsible for various illnesses, they have explored ways to correct the underlying genetic defect. Cystic fibrosis has commanded much of their attention.
Since August 1989, scientists have succeeded in finding the gene responsible for CF, figured out how it causes the disease, corrected the defect in a test tube, and devised and tested, in animals, a way to deliver a healthy, working copy of the gene to the lungs, using a cold virus as a vehicle.
The success of the animal experiments prepared the way for gene therapy in humans. The human experiments are aimed at correcting the genetic defect that causes an imbalance of salt and water in cells lining the airways of CF patients. That chemical imbalance causes the buildup of mucus.
In the experiments, researchers will manipulate a cold virus so it can no longer reproduce. Then they will stitch into the virus a healthy copy of the CF gene.
Millions of these altered viruses will be dripped into the lungs by way of a liquid. Once there, the viruses, with the cystic fibrosis genes in tow, will invade the lung cells and set up shop. The healthy CF genes should then direct the cells to function normally.
It was Ronald Crystal, chief of the pulmonary branch of the National Heart, Lung and Blood Institute in Bethesda, Md., who came up with the idea of using a cold virus as a vehicle - a delivery truck, he likes to say - for transporting healthy CF genes into the body.
He says the idea came to him one day 3 1/2 years ago while he was out jogging and thinking about a conversation he'd had with a French researcher.
Crystal figured that a type of cold virus called an adenovirus would be a good way to infiltrate the lungs of CF patients, because the virus already does just that when it infects someone with a cold.
"It just suddenly struck me it would be a way to cure cystic fibrosis by gene therapy," Crystal said.
In recent years, Crystal and other researchers have begun testing several promising new drugs for cystic fibrosis, such as amiloride and DNase, to treat the symptoms of the disease. But they don't address the underlying defect. That's why the three gene-therapy trials are so important. They raise the possibility, for the first time, that a way can be found to cure this fatal disease by overcoming the underlying cellular disorder that causes it.
Crystal's experiment will involve 10 patients. Wilson's at Penn will include a dozen. The University of Iowa experiment, under the direction of Dr. Michael Welsh, differs slightly from the others in that the virus will only be
put in the nasal passages, not the lungs, of patients. Three patients will be involved in this trial, in which Iowa scientists are collaborating with Genzyme Corp.
A gene therapy for CF would probably end up being something patients would have to take periodically for the rest of their lives. Crystal said he did not yet know how large a dose patients would need or how often they would need it.
"If we're going to make gene therapy widespread, it's going to have to be like a pill in a bottle," he said. "We can take it or inject it or give it in an aerosol spray."
Kelley said gene therapy today was about where aviation was in the early 20th century.
"But I'm convinced that gene therapy is the way to go. I think it will have a major impact on people's health. And I'm putting my money on it."