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| GENE THERAPY | |
 December 8, 1999 
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The Health Unit is a partnership with
the Henry J. Kaiser Family Foundation.
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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
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, 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. |
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| A sudden breakthrough | ||||||||||||||||||||
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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.
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.
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. |
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| A safe procedure? | ||||||||||||||||||||
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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.
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. 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.
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. |
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| The preliminary findings | ||||||||||||||||||||
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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.
SUSAN DENTZER: Jesse Gelsinger's father, Paul Gelsinger, had this to say about the researchers at Penn.
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: 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.
SUSAN DENTZER: At today's RAC meeting, participants reported on new findings on adenoviruses. Tomorrow they will take up the Gelsinger case. |
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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.
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.
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. 
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. 
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. 
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. 
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: 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. 
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.
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: 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. 
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. 
