Gene Therapy

Perhaps nothing has become as synonymous with futuristic medicine as gene therapy. But, as brought home by the recent death of a young research subject at the University of Pennsylvania, the dangers are still not well understood. The investigation into the death of 18-year-old Jesse Gelsinger revealed that it probably wasn't the genes he was getting that caused his death. Rather it appears that the death was the result of the delivery vehicle for those genes - in this case a virus modified so it wouldn't cause an infection.

For a quarter of a century, gene therapy has been stymied, largely because the patient's immune system attacks the treatment as a suspected rogue - or because it actually does turn rogue. Now, University of Pennsylvania researchers have convincingly shown that they can overcome these formidable obstacles. Cells that were genetically modified to fight HIV have persisted for up to 11 years - and counting - without bad side effects in 41 patients. In two other patients, the modified cells were safe but not as durable, according to the Penn study, published last week in Science Translational Medicine.

We have entered a new era of super-hyped science, personal glory seeking, and overnight millionaires from biotech speculation - the sort of atmosphere that leads to the "snake-oil" overselling of medical treatments. Now comes a disturbing indictment of the most publicized and promising field of medical science, gene therapy. That's the hopeful term for treating cancer, cystic fibrosis and other diseases by replacing defective or missing genes. It comes from a committee of physicians and scientists appointed by the National Institutes of Health (NIH)

In recent months, researchers in Philadelphia and beyond have reported success using gene therapy to treat common, intractable cardiac problems including heart failure, hardened arteries, and the racing heartbeat known as atrial fibrillation. You probably haven't heard about these feats because they were in pigs, dogs, or sheep. In the most complex mammal of all - humans - the results of cardiac gene therapy experiments have been encouraging, but inconclusive. That's not unusual in the early stages of clinical testing, but it is frustrating for the dogged researchers who believe the field is close to a breakthrough.

In a feat that is renewing hopes for conquering AIDS, researchers have genetically engineered patients' vital immune cells to make them resistant to HIV infection. To confer this invulnerability, scientists took the immune cells from HIV-positive patients' own blood, then snipped out a single gene - the first time such a precise alteration has been achieved on a meaningful scale. When put back in the patient, the cells no longer make a receptor that HIV needs to enter the cell, effectively blocking the virus.

The malady is as grueling as it is costly, marked by debilitating internal bleeds that require frequent injections at a cost of $100,000 a year or more. When such treatments are unavailable, as in much of the developing world, the disease is a childhood killer. Yet new gene-therapy research holds out the promise that this bleeding disorder, hemophilia B, could someday be defeated with just one shot. That is the finding of a study led by hematologist Katherine A. High at the Children's Hospital of Philadelphia, published last week in the online edition of the journal Nature.

In a development that may overcome a major stumbling block to gene therapy, scientists at the University of Pennsylvania Medical Center have figured out how to turn the treatment gene on and off in mice and monkeys. Such control over therapy is crucial. Too much medicine can be as dangerous as the disease itself. "Ideally what you want to be able to do is to turn the gene on when you want to and switch it off when you don't want it," said French Anderson, director of the gene-therapy laboratories at the University of Southern California.

In another attempt to reopen its stalled gene-therapy clinical trials, the University of Pennsylvania again defended its conduct of a trial that caused the death of an Arizona teenager last year. In response to a March 3 warning letter from the federal Food and Drug Administration that detailed a number of problems with the trial, Penn and its Institute for Human Gene Therapy yesterday said numerous measures were underway to prevent the problems from reoccurring. In a 14-page letter to the FDA, the institute, led by scientist James M. Wilson, said it had contracted with an independent company, Parexel International Corp.

Scientists have developed a genetic technique that may make it possible to treat people suffering from cystic fibrosis and other deadly lung diseases by spraying aerosols into their throats. The treatment represents a dramatic advance in the exploding field of gene therapy - the altering of genetic material in a patient's cells. In a study being published today in the journal Science, researchers said they used the treatment to transfer a human gene into the lung cells of rats.

Donald appeared much more relaxed than the researchers watching from the edges of the operating room as nurses and anesthesiologists readied him for surgery. He was about to undergo a revolutionary cancer treatment, and the scientists had reason to be tense. They were trying a new form of gene therapy and didn't know how dangerous it was or whether it would work. Donald, 64, was a retired asbestos worker with less than two years to live. He was being killed by mesothelioma, a rare cancer that attacks the membranes covering the lungs and the opposing chest wall.

For a quarter of a century, gene therapy has been stymied, largely because the patient's immune system attacks the treatment as a suspected rogue - or because it actually does turn rogue. Now, University of Pennsylvania researchers have convincingly shown that they can overcome these formidable obstacles. Cells that were genetically modified to fight HIV have persisted for up to 11 years - and counting - without bad side effects in 41 patients. In two other patients, the modified cells were safe but not as durable, according to the Penn study, published last week in Science Translational Medicine.

ATLANTA - In what's being called a landmark study, researchers used gene therapy to successfully treat six patients with severe hemophilia, a blood-clotting disorder. The study was preliminary and involved only six patients, and other promising early attempts to use gene therapy against hemophilia ultimately failed. But a single infusion using the new treatment worked in some patients for more than a year, boosting their clotting ability significantly. "I think this is a terrific advance for the field.

In recent months, researchers in Philadelphia and beyond have reported success using gene therapy to treat common, intractable cardiac problems including heart failure, hardened arteries, and the racing heartbeat known as atrial fibrillation. You probably haven't heard about these feats because they were in pigs, dogs, or sheep. In the most complex mammal of all - humans - the results of cardiac gene therapy experiments have been encouraging, but inconclusive. That's not unusual in the early stages of clinical testing, but it is frustrating for the dogged researchers who believe the field is close to a breakthrough.

With his blood cancer progressing and standard chemotherapies no longer working, the patient decided to try an experimental gene therapy at the University of Pennsylvania. Twenty-two days after getting a very low dose, he had to be hospitalized because of toxic effects on his kidneys and liver - a problem the researchers had anticipated but considered unlikely. And then, the very next day, something happened that the researchers had not anticipated, despite 20 years of refining the treatment.

The malady is as grueling as it is costly, marked by debilitating internal bleeds that require frequent injections at a cost of $100,000 a year or more. When such treatments are unavailable, as in much of the developing world, the disease is a childhood killer. Yet new gene-therapy research holds out the promise that this bleeding disorder, hemophilia B, could someday be defeated with just one shot. That is the finding of a study led by hematologist Katherine A. High at the Children's Hospital of Philadelphia, published last week in the online edition of the journal Nature.

In a feat that is renewing hopes for conquering AIDS, researchers have genetically engineered patients' vital immune cells to make them resistant to HIV infection. To confer this invulnerability, scientists took the immune cells from HIV-positive patients' own blood, then snipped out a single gene - the first time such a precise alteration has been achieved on a meaningful scale. When put back in the patient, the cells no longer make a receptor that HIV needs to enter the cell, effectively blocking the virus.

Corey Haas used to need a high schooler to accompany him on the soccer field, to point out where the ball was. Whenever the 9-year-old played with his Lego blocks, he had to feel around for them. At school in Upstate New York, he needed the help of a teacher's aide and a special computer screen to display class materials in giant size. Not anymore. A year and a half after reporting that it could restore some vision to young adults who have a rare form of blindness, a team of Philadelphia researchers announced yesterday that its gene therapy works even better in children.

After almost a decade of reflection, University of Pennsylvania researcher James M. Wilson says problems with the gene-therapy experiment that killed an Arizona teenager were "absolutely unacceptable" and ultimately "my responsibility. " "I have tried to admit where I did wrong, where I fell short," Wilson, 53, said this week in his first media interview about Jesse Gelsinger's death in September 1999. "I have tremendous regrets about what happened. I feel absolutely awful about what it has done to the family, to this university, to the field.