United States: The Triumphs And The Ongoing Tribulations Of Gene Therapy

Biotechnological advances are usually greeted with a mixture of euphoria and apprehension. Such is the case with gene therapy.

Last week, an article in Science reported that two children born with life-threatening immune system disorders that had necessitated living within protective sterile "bubbles" were healthy almost a year after receiving a gene therapy treatment administered by a French scientific team. The team also reported that, of three other infants treated recently (including one from the United States), at least two were now completely healthy.

These successes were publicized against the backdrop of the continuing suspension of many gene therapy trials in the U.S. as a result of the shadow cast over the entire field by the death a few months ago of a healthy participant in a gene therapy trial conducted at the University of Pennsylvania. Several U.S. government agencies continue to squabble over who should regulate gene therapy experiments and how this should be done, adding to the confusing picture.

Gene therapy can be described in a deceptively straight-forward manner: a disease derived from an abnormal gene can be cured by giving the patient a normal replacement gene carried by a delivery vehicle, or vector, typically a virus.

The children treated by the French team were born with a rare and deadly disease called SCID - XI, caused by a defective gene that disables the body's T cells, which are essential to the immune system's ability to fight infections.

The French scientists removed cells from their patients' bone marrow, and then exposed these cells to a virus carrying normal copies of the gene that the children were missing. The cells were then re-infused into the children, and within 15 days the cells multiplied to produce normal immune system cells containing the missing gene.

Over time, the children regained their health. Their chronic skin sores and diarrhea disappeared. When they were vaccinated with standard tetanus, diphtheria and polio shots, their immune systems performed as they should, producing antibodies against these infections, which would previously have killed them. Four out of the five children have left their isolation tents and are living at home, leading normal lives for the first time.

This remarkable success story should not be overstated, however, since it is one of only a small number which have occurred during the scientific community's roughly 10-year experience with gene therapy. The task of choosing the right vector to deliver the replacement gene to the correct place in the body while not creating a life-threatening immune reaction in the patient has proven devilishly complex for most diseases.

For example, certain viruses (retroviruses) are intended to deliver their genetic material into a patient's chromosomes, but they can only deliver a gene to a cell that's dividing; the liver and spleen, where many viral vectors end up, have few dividing cells.

Other researchers have tried adenoviruses, a source of the common cold, which have the ability to infect both dividing and non-dividing cells with a replacement gene. Unfortunately, the immune system is sensitive to this type of virus, and it has been known to attack cells containing adenoviral-delivered genes. In fact, it was an adenoviral virus that killed Jesse Gelsinger, the University of Pennsylvania clinical trial subject.

Other companies are experimenting with adeno-associated virus, which is a different virus that the immune system largely ignores, or synthetic vectors, which also don't trigger an immune response.

Each of these vectors are being tried in many of the roughly 200 studies that are still being permitted to continue in the U.S. today, but a clear winner for all diseases has yet to emerge.

The mapping of the human genome, meanwhile, is providing many new genes for these vectors to transport, accelerating the usefulness of gene therapy. The scene is reminiscent of antibiotic development in the late 1920s, where after years of research the discovery of penicillin began an era of multiple miracle drugs that eradicated many infectious diseases for which there was previously no cure. Antibiotics revolutionized medicine and gene therapy could as well, if given appropriate time to mature.

Most patients who receive gene therapy are fatally ill and have no alternative, hence death is not a surprising phenomenon. If a problem develops in a clinical trial, it is important to differentiate among the many factors which could have caused the problem other than the treatment itself, such as the overall health of the patient, the trial design (i.e., the dosage level of the drug), and whether the design was adhered to.

What is remarkable about the clinical trial resulting in the death of Jesse Gelsinger is how many things were concurrently performed in an inappropriate or unprecedented manner.

Among the 14 protocol violations which were found by the FDA, the lapses included:

• the inclusion of a healthy patient (Jesse) in the study, even though he did not meet the eligibility criteria, and
• the failure of the trial coordinators to take heed of the fact that two other patients in the trial previously developed adverse, toxic reactions to the therapy, followed by a second equally serious failure not to incorporate this data into exclusion criteria for subsequent patients.

The nature of the informed consent obtained from Jesse was equally alarming. Had he known that monkeys had died from the therapy before it was given to humans and that several previous participants had suffered serious toxic reactions to the treatment, would he have agreed to take part in the trial?

In characteristic Washington fashion, accusations flew in all directions. The FDA criticized the University of Pennsylvania. Meanwhile, the Recombinant DNA Advisory Committee (RAC) - established to advise the National Institutes of Health on ethical and public policy issues but without formal authority - seized on the opportunity to try to expand its power and requested authority to review reports on adverse clinical trial events, which companies are required to file with the FDA.

FDA filings are confidential since they include detailed proprietary information about a company's clinical trial protocols and future plans. Nevertheless, a debate ensued as to whether these filings should be made a matter of public record.

The industry trade organization, BIO, tried to broker a compromise between the positions held by the RAC and the FDA by proposing that their members might be willing to provide to the RAC the same data which they provide to the FDA, so long as it would be subject to similar confidentiality protections. The dialogue, did in fact, result a few weeks ago in new, stricter guidelines for reporting adverse clinical trial results to the government, although there is still considerable jostling among the various government agencies over who will enforce the guidelines and the implications for non-compliance.

Expanded government regulation is certainly a reasonable response to a failure of the private sector to police itself, if the failure is widespread. However, the Gelsinger case was unique in the degree to which clinical protocols were not followed and clinical results were not factored into the ongoing administration of a trial. Add to this the lightning-rod quality of gene therapy research, which many people have doubts over and for which clinical success is perhaps now overdue. As was the case for antibiotics many years ago, tolerance for mistakes and patience may be necessary ingredients for the continued advance of medical science.