GENE THERAPY.

Balancing the Promise With the Reality

On September 17, 1999, four days after receiving a gene therapy infusion at the University of Pennsylvania, a young man from Arizona who had a genetic disease known as Ornithine Transcarbamylase Deficiency (OTC) died. His death--the first that could be directly linked to gene therapy--electrified the scientific community and triggered a national debate that will have a powerful impact on the future of gene therapy experiments and how they are approved and monitored. These are profound and important questions left unanswered, but for Jesse Gelsinger, the 18-year-old who died, and perhaps for others, it is a debate that came too late.

WHAT IS GENE THERAPY?

The concept of gene therapy was born when scientists theorized that if they could replace faulty genes with good ones, they would be able to cure hereditary disorders. The problem was how to get good genes into cells. Scientists knew that cells were masterful at protecting themselves, and that it would be important to insert new genes in a way that left them intact and able to function. They realized that one of the few entities that could enter a cell and reside inside for a long period of time was a virus. Thus, they launched a series of animal experiments using a genetically modified virus (called a "vector") that would carry a desirable gene, much like a passenger in a taxi, and drop it off in the targeted cell. To assure that the virus would not multiply and cause disease in the recipient, they modified it so it could not replicate after it delivered the gene.

During the 1980s, scientists working in this field realized that if gene transfer worked in humans, it would raise profound moral and ethical questions. Gene therapy, they theorized, could change the human race if there were no ethical parameters and no regulatory boundaries that scientists would have to obey. Moreover, designing new viruses would trigger environmental questions that could potentially pose new risks to humanity. In light of all this, they met together and proposed that the government should create an oversight structure called the Human Gene Therapy Subcommittee of the Recombinant DNA Advisory Committee (which is known as the "RAC"), to review pending gene therapy experiments and monitor the progress of the technology. These scientists felt that if gene therapy experiments were reviewed and discussed in open meetings by ethicists, scientists, and members of the public, it would build public trust and reduce fear of genetic engineering. The major threat to the future of gene therapy, they surmised, would be public suspicion that experiments conducted behind closed doors might lead to the creation of genetically engineered humans, potentially turning frightening science fiction into reality.

GOVERNMENT REGULATION

As a result of these recommendations, the National Institutes of Health (NIH) created the Human Gene Therapy Subcommittee, which developed a list of rules that scientists would have to abide by before, during, and after they transferred new genes into humans. These rules are parts of the "NIH Guidelines for Research Involving Recombinant DNA Molecules," and they are known as the "Points to Consider." The rules must be obeyed by all scientists who receive federal funds, as well as by private companies when treatment of patients is provided at a hospital that receives federal funds, such as Medicare or Medicaid. After the RAC would approve a protocol, scientists would have to obtain FDA approval before an experiment involving humans could begin.

EARLY TRIALS

Even though gene therapy was conceived as a technology that would treat or cure genetic diseases, within a short period of time, the great majority of experiments focused only on cancer. This was primarily because gene therapy experiments are very expensive, and the NIH was not generous in its funding to academic investigators who wanted to pursue gene therapy. The federal government funded only three vector manufacturing facilities, so the private sector stepped in, and pharmaceutical companies sponsored trials at an increasing rate each year. Pharmaceutical companies know that genetic diseases are generally rare, and there would be much bigger and more lucrative markets for products to treat common diseases such as cancer or heart disease. As a result, the field turned away from the genetic diseases it was most likely to cure, and moved toward diseases for which it was easiest to get funding. By September, 1999, the RAC had approved 295 gene therapy protocols, 206 of which were for cancer.

The first human trial of gene therapy was for Severe Combined Immune Deficiency (SCID), more commonly known as the "Bubble Boy Disease" because of the young Texas boy who lived for years in a plastic bubble that protected him from germs. However, just before the SCID experiment was launched, a pharmaceutical company had developed an "orphan drug" that replaced the missing enzyme (adenosine deaminase) in children with this disease. Thus, this type of SCID was no longer an untreatable and deadly genetic disorder, so the RAC required the investigators to continue giving the children the drug until they could prove that the transferred gene made injections of the enzyme unnecessary.

This initial gene transfer protocol received extraordinary publicity, and even today the public believes it was successful. In terms of transferring the needed gene, it was indeed successful; but, the fact is, the new genes were unable to manufacture enough of the enzyme to make any difference in the children. Even now, the children with SCID who have received gene therapy treatments still rely on the injectable enzyme. However, the positive news about this experiment became a pattern that persisted in the news media: report the good news and ignore the negative facts.

In time, the Gene Therapy Subcommittee was merged into the RAC, and even today the RAC continues to review gene therapy protocols in a public forum every three months. Every six months, the RAC is given a report on the progress of all approved protocols. These reports are supposed to disclose how many patients have been enrolled in each, any adverse events that have occurred, and the causes of any deaths. However, over time, as the RAC would review the progress reports, its members noticed that few adverse events were being reported, and several critical questions were not being answered.

For one thing, probably because the great majority of experiments have been on terminal cancer patients, there have been many deaths. However, there is no way to tell for certain whether the deaths are in any way related to the gene transfers. This is because one would reasonably expect that terminal cancer patients would die of cancer if the gene transfer did not help them. Also, to date, gene therapy has not been therapeutic, no one has been cured, perhaps because of the efficiency of the human immune system. Since most experiments have used vectors called "adenoviruses"--viruses that cause common colds in humans--an immune response would naturally be triggered to destroy the virus and its passenger, the new gene.

Furthermore, the NIH Points to Consider require that, in the event of a patient's death (for any reason, whether related to the gene therapy or not), an autopsy will be requested to determine whether the vector or transferred gene played any role in the death, and whether the new gene reached the patient's reproductive organs (which might indicate unintended consequences for future generations). These are important questions. But today, after approximately 3,000 humans have participated in gene transfer experiments, only a handful of autopsies have been done.

THE PUSH TOWARD DEREGULATION 

During the mid 1990s, the pharmaceutical industry complained that too much time was being wasted in the RAC review process. So the NIH was completed to change the rules. Experiments that were not unique, and those that used vectors that had already been utilized in numerous other experiments, would no longer have to be reviewed by the RAC in a public forum. They would go directly to the FDA. Only novel protocols using new vectors, or experiments on new diseases that were not previously the subject of gene therapy investigations, would continue to be reviewed by the RAC.

Once a protocol goes to the FDA, it becomes enshrouded in protective secrecy because the FDA considers all information a "trade secret" unless the sponsor agrees to release data. Since most gene therapy protocols were simply duplications of experiments already under way, there was no protest against this change of the rules. Although many people asked why there was a need to rush experiments that had shown no therapeutic benefit, there was no formal objection registered to trigger a public dialogue about this change in NIH rules.

Biotechnology companies complained that the RAC was unduly restrictive. The industry said it was regulated by the FDA, and therefore it was improper for the NIH to impose its rules on private companies. To everyone's surprise, in the spring of 1995, the NIH director, Dr. Harold Varmus, announced that he was going to dissolve the RAC. This meant that there would be no further public discussion and no public input into gene therapy investigations. If a scientist decided to transfer genes to make a person taller, or smarter, or change his hair or skin color, there would be no opportunity for ethical objections. Investigators could stop pursuing cures for diseases and redirect their studies to cosmetic gene therapy, which might ultimately threaten the diversity of the human race through engineering of "designer children."

Doctor Varmus' announcement provoked an outcry, not only in the United States, but around the world. Other countries admired what the RAC was doing, and they had created their own RAC-type regulatory bodies to monitor gene therapy experiments. When members of Congress protested, Dr. Varmus changed his mind. One year later he announced that he would reduce the RAC from 25 members to 15, and no longer allow them to vote for or against approval of protocols. However, the RAC would continue to exist. The weakened Committee's only remaining tool was to serve as a pulpit against scientific excesses.

Between December 1995 and December 1996, there were no RAC meetings while a political battle raged among the NIH, Congress, and the public. One of the last protocols that the RAC approved, before its meetings were halted in 1995, was for a genetic disease called Ornithine Transcarbamylase Deficiency (OTC), which is a rare urea-cycle disorder. The urea-cycle disorders are characterized by enzyme deficiencies or enzyme abnormalities that can cause excessive elevations of ammonia in affected individuals. Children with this disorder go into a coma and they usually die. However, an orphan drug is now available to treat many of the ureacycle disorders, including OTC. If an individual with a mild genetic defect for OTC takes the medicine and follows a strict diet, he or she may live a nearly normal life.

The scientists who proposed the study wanted to inject the vector (an adenovirus) into the artery leading to the liver of individuals with OTC deficiency, and they wanted to do the experiment on children. The RAC disagreed. Because OTC Deficiency was a treatable disease, the RAC told the investigators they had to do the experiment on adults (over 18 years of age), and they could not put the vector into the liver because of concern that it might cause a severe reaction. Instead, the RAC told the investigators to put the vector into a vein via intravenous infusion. The scientists agreed to make these changes, and the newly designed protocol was approved.

CRISIS TRIGGERS REFORM

Following Jesse Gelsinger's death, an autopsy confirmed that the adenovirus had triggered an overwhelming attack by his immune system which destroyed his liver and other organs. Within days, the Washington Post reported that at least six more deaths had occurred in other gene therapy experiments that had not been reported to the RAC. Additionally, the FDA was aware of several deaths and severe adverse events from gene therapy that were not reported to the RAC. The sponsors of those studies claimed these were "trade secrets," and refused to allow the FDA to release the information. Moreover, even though the investigators on the OTC experiment were required to report any changes to the protocol after the RAC reviewed it, they did not inform the RAC that they had decided to infuse the vector into the liver despite the RAC's instructions not to do so.

The tragic death of Jesse Gelsinger has raised many profound questions that will haunt the field of gene therapy for years to come. Why haven't investigators and companies obeyed the RAC's reporting rules? Why have they kept important information secret? Why have only the positive results been released to the news media? Under what circumstances can a company ethically claim that a death is a "trade secret?" With the potential to alter the human race, who's purpose is served if this research is done behind closed doors? And, most of all, why have two critical government agencies--the FDA and the NIH--competed instead of cooperated when lives were at stake?

The industry may have felt that it was important to claim success prematurely because this is the only way to raise investment capital. But, by withholding the truth, they were not being honest to their stockholders, or to the brave patients who volunteered to participate in clinical trials. Many patients were led to believe that, while gene therapy technology does not work very efficiently, at least it is safe. If adverse events were not reported to the RAC, as required patients who considered participating in the trials had no way to learn the truth. For example, in the OTC experiment, three patients who had participated before Jesse Gelsinger had abnormal liver enzyme tests after the vector was infused, and several monkeys had died before the vector was given to humans. However, these facts were hidden from potential participants, and not reported to the RAC until after Gelsinger died.

A major aim of the RAC is to share information so that mistakes can be avoided by other gene therapy scientists around the world. In that way, precious resources will not be wasted duplicating experiments that have already been done. It is not yet clear whether Dr. Varmus' attempt to dissolve the RAC in 1995 encouraged investigators to ignore the RAC's rules and hide the truth in the field of gene therapy. Why was the private sector allowed to dominate the field when the NIH knew that much more basic research was needed to make gene therapy safer and more effective?

The soul searching that has occurred since the Gelsinger death marks a turning point in gene therapy research. It has made the value of the RAC more obvious and the importance of public participation in research dialogue painfully clear. History has shown that scientists will sometimes go to extraordinary lengths to test their hypotheses, sometimes overlooking patient protections. As a society, we cannot allow gene therapy scientists to perform experiments in secret that could affect future generations of unborn children, just because they want to prove a point.

Other troubling issues persist, however. Some see the day when "designer children" become a reality, and parents will be able to choose their babies' eye and hair color, IQ, height, and weight. While most people feel this concept is distasteful, some are eager and willing to pay for the privilege. In a country that does not even guarantee every citizen the right to health insurance, one can only imagine the widening medical gap between rich and poor if we could buy access to a technology that would change our genes. For example, who will decide which skin color is preferable? Will those who do not have the proper skin color suffer as outcasts? Will diversity eventually become a crime?

Ultimately, it is the way this gene therapy controversy has affected patients that is most disturbing. During the past decade, families with hereditary diseases felt it would soon be possible to replace faulty genes with good ones, so that future generations could be born disease-free. Now they know this is not true, and the dream is not yet a reality. It may take another decade or more before safe and effective gene therapy can be developed with new vectors that will not arouse the immune system. The best thing that can come out of the tragic death of Jesse Gelsinger is that patients who volunteer for clinical trials will be treated honestly, so they understand the risks. Scientists and corporations will be more sensitive to the public's need to know what they are doing, and finally, families will not base important medical decisions on news reports that were aimed at Wall Street and only accidentally filtered down to Main Street.

Someday gene therapy will accomplish all the miraculous medical achievements it was conceived to do. But when this happens, we will learn about it from peer-reviewed medical journals, not the nightly news. And when gene therapy is finally deemed safe and effective, the challenge will be to confine its use to the treatment and cure of diseases, thus preventing re-engineering of the human race.

Abbey S. Meyers is the founder and president of the National Organization for Rare Disorders (NORD). Ms. Meyers was a member of the NIH Gene Therapy Subcommittee from 1989 to 1992, and the Recombinant DNA Advisory Committee (RAC) from 1993 to 1996. She served as the consumer representative on these committees. She has three children with a genetic disease, and five grandchildren who are "at risk" of inheriting it.