December 8, 1999
The Health Unit is a partnership with
the Henry J. Kaiser Family Foundation.
RAY SUAREZ: Now, an inquiry into the developing science of gene therapy,
reported by Susan Dentzer of our health unit, a partnership with the
Henry J. Kaiser Family
SUSAN DENTZER: Ever since the notion of gene therapy first surfaced in the 1980s, the prospects have been tantalizing. Scientists had already determined that much of human disease had its root in faulty or even missing genes. So it seemed only natural that they begin looking to prevent or cure illness by injecting healthy copies of genes into the body.
DR. FRENCH ANDERSON: We then went through a period of great enthusiasm and optimism.
SUSAN DENTZER: Dr. W. French Anderson is director of gene therapy at the University of Southern California's medical school. A preeminent researcher in the field for more than two decades, he presided over the first experimental treatment of a human in 1990. The patient was then-four-year-old Ashanti DeSilva, who suffered from a condition known as severe Combined Immune Deficiency, caused by a defective gene. To cure her, Anderson and his colleagues took healthy copies of those genes, then injected them into viruses engineered to serve as gene-carrying messengers; then transferred the viruses into DeSilva's body.
DR. FRENCH ANDERSON: That was very successful. Ashi is now a delightful young lady. She leads a totally normal life, and she's grown up. That was now nine years ago. She's 13 years old, and delightful.
|A sudden breakthrough|
SUSAN DENTZER: Based on DeSilva's case, newspapers and magazines hailed gene therapy as a breakthrough, but the initial euphoria about gene therapy has been tempered by subsequent events. The latest was the death last September 17th of Jesse Gelsinger. The 18-year-old died after undergoing gene therapy for a rare metabolic disorder at the University of Pennsylvania's Medical Center. His is the first death that has been directly attributed to the effects of the gene therapy rather than to the patient's underlying disease. Penn officials say Gelsinger's treatment sparked a severe reaction of his immune system, a so-called inflammatory response that caused multiple organs to fail. But the death has also raised scores of questions that are now the subject of a federal investigation. Dr. Kathy Zoon of the Federal Food and Drug Administration oversees the roughly 200 gene therapy clinical trials now underway in the United States. She told us that an FDA inquiry suggests that researchers at the university violated strict trial guidelines, known as protocols.
DR. KATHY ZOON: Right now we have preliminary evidence that there have been these protocol violations. But we need to confirm the information and thoroughly investigate it before we can actually have a complete understanding of what transpired.
SUSAN DENTZER: If these protocols had been followed, she says, Gelsinger may never have been enrolled in the experiment in the first place. And Zoon says it may be that the trials should have been halted for other reasons. Researchers at Penn denied that any protocol violations had taken place. While the investigation continues, events surrounding Gelsinger's death are receiving a thorough airing at a three-day meeting that began today. Taking place at the National Institutes of health in Bethesda, Maryland, the meeting was called by the Recombinant DNA Advisory Committee or RAC. That's a federally-appointed group of experts who advise the government on gene therapy research.
Gelsinger's death has also highlighted other important concerns in the field of gene therapy. These include alleged gaps in federal oversight and apparent delays by some researchers in reporting to the government when patients have had serious reactions. Abbey Meyers is president of the National Organization for Rare Disorders, which advocates for patients afflicted with many genetically-linked diseases. In the past, she has also served on the RAC.
ABBEY MEYERS: Things happened behind closed doors that should have been out for public discussion, public debate. It's raised so many questions about the science, about the ethics.
|A safe procedure?|
SUSAN DENTZER: This isn't the first time that the safety and effectiveness of gene therapy has been called into question. For all the hope that accompanied the first experiment on DeSilva, most subsequent gene therapy trials essentially failed to reverse disease. For example, patients with another genetic disease, cystic fibrosis, had such severe reactions to the therapy that trials were halted. And efforts to treat patients with advanced heart disease, cancer or AIDS didn't stop progress of the underlying illness.
DR. FRENCH ANDERSON: By about 1996 there had been about 300 clinical protocols approved and over 3,000 patients had been treated, and the vast majority died.
SUSAN DENTZER: One key problem dogged many of these trials: Failure to get healthy copies of genes into enough cells of the body to reverse the underlying disease. That led to a flurry of experimentation with the microscopic viral messengers that were being used to carry healthy DNA into the body. Researchers call these messengers vectors. One type of vector, or messenger, that proved very effective at transporting its genetic cargo was a common cold virus known as an adenovirus.
DR. FRENCH ANDERSON: Because it's a human virus -- many of us have adenovirus in our throats all the time -- because it's a human virus, it is able to get into a broad range of cell types.
SUSAN DENTZER: And the more viruses injected into the body, the better job they seemed to do at transporting genes. But high doses also ran the risk of irritating the body's immune system. Ultimately, this tradeoff between viral dose and effectiveness apparently played a role in the death of Jesse Gelsinger. In the mid-1990s, scientists at the University of Pennsylvania proposed using very high doses of the adenovirus in a clinical trial of patients with so-called OTC Disease. The disease is caused by a genetic defect that prevents the liver from ridding the blood of ammonia, a normal byproduct of metabolism. Although the disease can be controlled through diet and medication, in infants, in particular, it is often fatal. Researchers at Penn proposed to inject progressively higher dose of adenoviruses and genes into patients' bodies to determine the effects.
ABBEY MEYERS: The RAC had reviewed the protocol back in 1995, had decided that the protocol should not be approved.
SUSAN DENTZER: But the FDA disagreed on the basis of the scientific evidence and let the trial go forward. 17 patients with OTC then proceeded through the trial before Jesse Gelsinger.
DR. FRENCH ANDERSON: Seventeen patients had received the vector without problems, and this was the eighteenth and last patient. And it is still unknown why this patient had such a massive reaction.
|The preliminary findings|
SUSAN DENTZER: The FDA's preliminary findings suggest some possible reasons why. For example, the FDA's Zoon says tests performed on Gelsinger before he entered the trial showed that ammonia levels in his blood were too high. That could have meant that Gelsinger's liver was already functioning too poorly for him to have been admitted into the trial. What's more, Zoon says, earlier patients were having such toxic reactions to the increasingly high doses of adenovirus. As a result, under the agreed-upon protocols, the trials should have been stopped.
SUSAN DENTZER: If all of this is true and borne out in the rest of the investigation, it suggests that Jesse's death really was a needless death.
DR. KATHY ZOON: Well, I think we don't know that those deviations from the protocol could be causal. So that has to really be investigated very carefully and understood. But I think I am very concerned about how that was carried out, and how it affected the safety of the patient.
SUSAN DENTZER: Jesse Gelsinger's father, Paul Gelsinger, had this to say about the researchers at Penn.
PAUL GELSINGER: He was treated fine at UPenn. They did everything they could to help Jesse. What happened was totally unforeseen. They had no indication that anything would happen like what happened to Jesse.
SUSAN DENTZER: As profound as are these safety and ethical issues surrounding the Penn experiment, there is an equally strong desire on the part of many that experimentation in gene therapy continue.
ABBEY MEYERS: The one thing that Jesse's death should not do is stop gene therapy research. That would be the worst outcome.
SUSAN DENTZER: And in fact, for all the setbacks to date, gene therapy's potential still seems enormous. For example, these researchers at Georgetown University's Medical Center are experimenting with a gene known to suppress tumors, called P53. They inject the gene into mice that have been given human prostate cancer and that have also been treated with radiation. So far, the results appear dramatic, says biochemist Kathleen Pirollo of Georgetown.
KATHLEEN PIROLLO: You can see, compared to the tumors that we saw in the other animals, these tumors are virtually completely gone on these guys, and what we're hoping, and from what our past experience has been, that over the course of the next few weeks these tumors should completely disappear.
SUSAN DENTZER: Based on these results, the first clinical trial of this approach in humans with prostate cancer is expected to begin within a year. And still other patients, like 42-year-old David Lunneborg, are continuing to pin their hopes on gene therapy for treatment of cancer. He is undergoing gene therapy for melanoma, a deadly skin cancer, at the Mayo Clinic in Rochester, Minnesota.
DAVID LUNNEBORG: I am hoping it's a cure, but if it can just can keep it at bay for years or two years until there is a real true cure, that's that we're looking for.
SUSAN DENTZER: At today's RAC meeting, participants reported on new findings on adenoviruses. Tomorrow they will take up the Gelsinger case.