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Back To Vidyya Human Gene Therapy:

Harsh Lessons, High Hopes

A 4-year-old girl named Ashanthi DeSilva from the suburbs of Cleveland lay on crisp white hospital sheets with a needle stuck in a vein. She didn't mind; this happened all the time in her chronically sick childhood. At the other end of the intravenous hookup hung a clear plastic bag of very special cells: her own white blood cells, genetically altered to fix a defect she inherited at birth.

W. French Anderson, M.D., and his colleagues R. Michael Blaese, M.D., and Kenneth Culver, M.D., all then working at the National Institutes of Health, crossed a symbolic threshold with Ashanthi DeSilva that day, becoming the first group to begin a clinical trial in the new frontier of medical treatment: human gene therapy.

The reason for the excitement was simple: Most diseases have a genetic component and gene therapy holds the hope of curing, not merely treating, a broad range of ailments, including inherited diseases like cystic fibrosis and even chronic conditions like cancer and infectious diseases like AIDS.

At least, that's the theory.

In the 10 years since that first genetic treatment on Sept. 14, 1990, the hyperbole has exceeded the results. Worldwide, researchers launched more than 400 clinical trials to test gene therapy against a wide array of illnesses. Surprisingly, cancer has dominated the research. Even more surprising, little has worked.

"There was initially a great burst of enthusiasm that lasted three, four years where a couple of hundred trials got started all over the world," says Anderson, now at the University of Southern California in Los Angeles. "Then we came to realize that nothing was really working at the clinical level."

Abbey S. Meyers, president of the National Organization for Rare Disorders Inc., an umbrella organization of patients' groups, is much more blunt. "We haven't even taken one baby step beyond that first clinical experiment," Meyers says. "It has hardly gotten anywhere. Over the last 10 years, I have been very disappointed."

And then things got worse.

In September 1999, a patient died from a reaction to a gene therapy treatment at the University of Pennsylvania's Institute of Human Gene Therapy in Philadelphia. Jesse Gelsinger, an exuberant 18-year-old from Tucson, Arizona, suffered from a broken gene that causes one of those puzzling metabolic diseases of genetic medicine. An optimistic, altruistic Gelsinger went to Philadelphia to help advance the science that might eventually cure his type of illness. Instead, the experiment killed him.

In the aftermath of his death, there has been a flurry of activity to minimize the chance of future accidental deaths. The Food and Drug Administration, along with the National Institutes of Health, launched several investigations of the University of Pennsylvania studies and others. The inquiries provided disappointing news: Gene therapy researchers were not following all of the federal rules requiring them to report unexpected adverse events associated with the gene therapy trials; worse, some scientists were asking that problems not be made public. And then came the allegations that there were other unreported deaths attributed to genetic treatments, at least six in all.

"Probably the clearest evidence of the system [to protect research subjects] not working is that only 35 to 37 of 970 serious adverse events from [a common type of gene therapy trial] were reported to the NIH" as required, says LeRoy Walters, the recently retired head of the Kennedy Institute of Ethics at Georgetown University and former chairman of NIH's Recombinant DNA Advisory Committee. "That is fewer than 5 percent of the serious adverse events."

The news hit the clinical trial community like a thunderclap. The consequences have been immediate and wide-ranging, and may threaten future research.

"Participation in gene therapy trials is way down because the public is not sure what to make of this," says Philip Noguchi, M.D., director of the Cellular and Genetic Therapy Division in FDA's Center for Biologic Evaluation and Research (CBER). "They want to know what the government is doing to help restore the confidence in this field."

Responding to the Crisis

The federal government moved quickly to do just that. FDA immediately shut down the trial in which Gelsinger had volunteered, and all clinical gene transfer trials at the University of Pennsylvania in January. The university went on to severely restrict the research of its once-high-flying gene therapy institute director James Wilson, M.D., announcing in May that all his work would be confined to animal and laboratory experiments and that he would be barred from conducting studies in people.

FDA also suspended gene therapy trials at St. Elizabeth's Medical Center in Boston, a major teaching affiliate of Tufts University School of Medicine, which sought to use gene therapy to reverse heart disease, because scientists there failed to follow protocols and may have contributed to at least one patient death. FDA also temporarily suspended two liver cancer studies sponsored by the Schering-Plough Corporation because of technical similarities to the University of Pennsylvania study.

Moreover, as nervousness spread through the field in the months after revelations about Gelsinger's death, some research groups voluntarily suspended gene therapy studies, including two experiments sponsored by the Cystic Fibrosis Foundation and studies at Beth Israel Deaconess Medical Center in Boston aimed at hemophilia. The scientists paused to review their studies and make sure they learned from the mistakes made at the University of Pennsylvania.

In March, the Department of Health and Human Services announced two initiatives by FDA and NIH. The Gene Therapy Clinical Trial Monitoring Plan is designed to ratchet up the level of scrutiny with additional reporting requirements for study sponsors. A series of Gene Transfer Safety Symposia was designed to get researchers to talk to each other, to share their results about unexpected problems and to make sure that everyone knows the rules.

In addition, FDA launched random inspections of 70 clinical trials in more than two dozen gene therapy programs nationwide and instituted new reporting requirements. "We see the need to get the concept across that this is for keeps," says FDA's Noguchi. "You can be sloppy when you are dealing with a scientific paper, but you can't be sloppy when you are dealing with a human. Everything matters."

So far, the inspections only suggest that one other program appears to be in trouble, he says, but by the fall, "We should be able to say accurately [what is] the state of the art of gene therapy and where it needs to improve."

Meanwhile, President Clinton announced more "new actions designed to ensure that individuals are adequately informed about the potential risks and benefits of participating in research ... and steps designed to address the potential financial conflicts of interest faced by researchers." In addition, the President said in May, "We are also sending the Congress a new legislative proposal to authorize civil monetary penalties for researchers and institutions found to be in violation of regulations governing human clinical trials." If the legislation passes, FDA will, for the first time for drugs and biologics, have the power to essentially fine researchers and their institutions, up to $250,000 and $1 million respectively.

"This is a clear message," HHS Secretary Donna E. Shalala, Ph.D., said in May, "that we intend to get serious."

A History of Special Concern

Genetic engineering has always worried the general public.

When scientists first learned to clone genes in the mid-1970s, public reaction ranged from antipathy to hostility. Opponents, fearing that genetically engineered bacteria might escape from a laboratory, shut down the research at Harvard University and the Massachusetts Institute of Technology for months. Twenty-five years ago, in response to public concern, American scientists organized a voluntary moratorium on certain types of gene engineering experiments until safety questions could be resolved.

To help assuage public concern, NIH created its Recombinant DNA Advisory Committee, the RAC--which most simply call the "rack"--to provide a forum for genetic engineering debates to take place in public. As a result, the general opposition subsided.

But the RAC could do little if scientists didn't follow the rules. The promise of gene therapy, the glory of being the first to cure human ills, led at least one very smart scientist to make a very questionable decision. In 1980, an ambitious hematologist at the University of California at Los Angeles tested his gene therapy ideas on patients in Israel and Italy after being denied permission to perform the tests in Los Angeles. The experiments, conducted by Martin Cline, M.D., failed to help his subjects, and they violated federal rules designed to protect research subjects, leading to severe censure of the California scientist.

Ethical issues aside, the bigger problem for gene therapy has been basic biology. It's difficult to get new genes into billions of target cells within the body. Once inserted, the new genes need to function. Frequently, the body suppresses gene expression, essentially turning the new genes off, or destroys the transplanted genes. Although techniques have improved, today's scientists still face these challenges. To solve the problems, independent researchers have sometimes devised their own remedies of unknown safety. FDA began paying careful attention to these laboratory constructs when researchers began to request permission to test them in people under Investigational New Drug applications.

"Early investigators were more mom and pop operations," Noguchi says. "They were individual investigators making their own products … Almost all of them went on clinical hold because there was a lack of product information." Before FDA could allow them to proceed, technical questions about safety had to be answered, and that took time.

Typically, scientific questions are answered in laboratory and animal studies, but, with gene therapy, clinicians have been anxious to test their ideas in people. Once the NIH physicians treated their tiny patient in 1990, researchers rushed to get into the game with human trials. At the halfway point in the decade, the field was not progressing well. Then-NIH Director Harold Varmus, M.D., himself critical of the gene therapy trials in people, created a committee to review NIH's investment in the field. Varmus wanted to know whether NIH should continue to invest so heavily in the new technology.

The committee's conclusions were bleak:

"While the expectations and the promise of gene therapy are great, clinical efficacy has not been definitively demonstrated at this time in any gene therapy protocol, despite anecdotal claims of successful therapy and the initiation of more than 100 ... approved protocols," concluded the ad hoc committee co-chairmen Stuart H. Orkin, M.D., of Harvard Medical School and Arno G. Motulsky, M.D., of the University of Washington in Seattle in December 1995. While they saw promise, they also saw challenges. "Significant problems remain in all basic aspects of gene therapy. Major difficulties at the basic level include shortcomings in all current gene transfer vectors and an inadequate understanding of the biological interaction of these vectors with the host."

To transfer a repair gene into a patient, the researchers must go through several steps. First, they must isolate the disease-related gene. Then it must be packaged in a vector, usually a disabled virus that cannot reproduce and cause disease, but that can act like a delivery truck to transport the gene inside the patient's cells. Once inside the body's cells, the new gene can begin to function and restore health.

But building an effective delivery truck hasn't been easy. Scientists started by using a type of mouse virus as a vector, engineered so that it cannot replicate itself, that easily infects human cells and integrates the new genes into the cell's chromosomes (structures in the cell that hold the genes). These mouse vectors, however, only infect dividing cells, so researchers switched to adenovirus, a type of human virus that causes the common cold. Because the adenovirus's own genes to reproduce itself have been removed, the remaining viral container is unable to cause an illness.

At least, that's the idea.

The Gelsinger Case

When Orkin and Motulsky reported on the technical limitations of gene transfer techniques five years ago, they virtually predicted problems in the clinic. During that same December meeting at which Orkin and Motulsky made their disheartening report, the RAC approved the University of Pennsylvania gene therapy trial for ornithine transcarboxylase deficiency (OTCD). FDA, too, allowed the study to proceed.

The treatment idea was fairly straightforward. OTCD occurs when a baby inherits a broken gene that prevents the liver from making an enzyme needed to break down ammonia. With the OTCD gene isolated, the University of Pennsylvania researchers packaged it in a replication-defective adenovirus. To reach the target cells in the liver, the Philadelphia scientists wanted to inject the adenovirus directly into the hepatic artery that leads to that organ. Some members of the NIH RAC objected, fearing that direct delivery to the liver was dangerous. Nonetheless, after a vigorous public discussion with the University of Pennsylvania researchers, the RAC voted for approval of the study.

At age 18, Jesse Gelsinger was in good health, but was not truly a healthy teenager. He had a rare form of OTCD that appeared not to be linked to his parents, but the genetic defect arose spontaneously in his body after birth. During his youth, he had many episodes of hospitalization, including an incident just a year before the OTCD trial in which he nearly died from a coma induced by liver failure. But a strict diet that allowed only a few grams of protein per day and a pile of pills controlled his disease to the point where he appeared to be a normally active teenager. With the encouragement of his father, Paul Gelsinger, Jesse volunteered for the study, and when he was initially evaluated, his medical condition qualified him to participate.

Gelsinger received the experimental treatment in September 1999. Four days later, he was dead. No one is really sure exactly why the gene therapy treatment caused his death, but it appears that his immune system launched a raging attack on the adenovirus carrier. Then an overwhelming cascade of organ failures occurred, starting with jaundice, and progressing to a blood-clotting disorder, kidney failure, lung failure, and ultimately brain death.

In its investigation, FDA found a series of serious deficiencies in the way that the University of Pennsylvania conducted the OTCD gene therapy trial, some more serious than others. For example, researchers entered Gelsinger into the trial as a substitute for another volunteer who dropped out, but Gelsinger's high ammonia levels at the time of the treatment should have excluded him from the study. Moreover, the university failed to immediately report that two patients had experienced serious side effects from the gene therapy, as required in the study design, and the deaths of monkeys given a similar treatment were never included in the informed consent discussion.

FDA's discussions with the university remain ongoing.

Signs of Progress

Not all the news about gene therapy is bad. It's true that dramatic cures have not been seen to date, but there are tantalizing signs that important advances may be just around the corner.

Ashanthi DeSilva, the girl who received the first credible gene therapy, continues to do well a decade later. She suffered a type of inherited immune disorder called Severe Combined Immune Deficiency, or SCID (pronounced skid), that left her susceptible to every passing microorganism. Without gene therapy, DeSilva would be living like David, the Boy in the Bubble, who had a similar disorder. Instead, the NIH researchers inserted a normal copy of the broken gene into some of her white blood cells, healing them, helping them function normally to restore her immune system. Cynthia Cutshall, the second child to receive gene therapy for the same disorder as DeSilva, also continues to do well.

Scientists, however, have discounted the benefit of the first gene therapies because the girls began receiving a new drug treatment that replaces the missing enzyme just before receiving the genetic therapy. And they continue to receive the drug after the genetic treatment, though gene therapy pioneer Anderson argues that since the drug dose has remained the same while their bodies have grown substantially over the decade, it makes a negligible contribution to their well being.

In April, French scientists reported convincing evidence that they successfully treated a different form of SCID (X-linked severe combined immune deficiency, the type suffered by the boy in the bubble) with gene therapy. Four of the first five babies treated by Alain Fischer, M.D., of the Necker children's hospital in Paris have had "a complete or near complete recovery" of their immune systems after the treatment.

Meanwhile, researchers at Children's Hospital of Philadelphia, Stanford University and Avigen, Inc., a biotech company in Alameda, Calif., have reported promising results in hemophilia B patients. The team packaged a gene for Factor IX, a blood clotting protein, in a defective adeno-associated virus (AAV). They then used the AAV to insert the gene into patients who suffered abnormal blood clotting because they lack Factor IX. Normally, these hemophilia patients needed to inject Factor IX to prevent uncontrolled bleeding. In June, the researchers reported treating six patients with the Factor IX gene therapy. Even though the dose of the gene therapy was so low that no one expected it to help, it reduced the number of injections of Factor IX that these patients used on an ad hoc basis.

"The hemophilia studies are looking promising," says FDA's Noguchi, "but will need further study to know whether it is an effective product."

These two studies suggest the power of genetic treatments.

"We do seem to have turned the corner," says Anderson, "and there are a number of clinical trials that are starting to show success."

Even as FDA increases its scrutiny of the field to ensure patient safety, there is a sense of advancement. "There is good progress being made," Noguchi says. "FDA thinks that gene therapy will work, but we don't know for which disease. The recent events in France show that if you have the right disease, and can insert the right gene, you can obtain good results."

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Editor: Susan K. Boyer, RN
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