Table of Contents
FDA Consumer magazine
September-October 2000
By Savio L.C. Woo, Ph.D.
The possibility of correcting human genetic disorders by gene therapy caught the imagination of the scientific community as well as that of the public long before the first clinical gene transfer experiment was launched ten years ago. During the ensuing decade, however, the extraordinarily high level of expectation has proven to be grossly optimistic. This prompted Dr. Harold Varmus, then Director of the National Institutes of Health, to appoint two separate committees in the mid-1990s to evaluate the field of gene therapy. The committees independently concluded that clinical applications of gene transfer could not possibly succeed without adequate scientific and technological support, as well as sufficient preclinical studies in relevant animal models of human disease to validate treatment efficacy.
The scientific community has taken these constructive criticisms to heart during the past few years, and dramatic progress has been made in the basic science of viral and non-viral vector development used to transfer genes into patients. As a result, some approaches appear to be working. The Hemophilia B trial currently being conducted at the Children's Hospital of Philadelphia and Stanford University employs intramuscular delivery of the gene expressing human Factor IX, a protein involved in blood clotting. Patients in this trial have exhibited much improved whole blood clotting times for months after the gene treatment. Children in Paris with X-linked SCID, an inherited disorder that destroys the immune system, are able to live at home normally after genetic treatment of bone marrow stem cells. While both trials are in early phases, the encouraging results do provide proof of the scientific principle that human genetic disorders can be corrected by gene transfer.
In September 1999, clinical experiments in gene transfer research suffered their first patient loss as a direct consequence of the gene treatment itself. The patient was a 19-year-old male with a metabolic disorder who received a high dose of a genetic treatment directly into his liver at the University of Pennsylvania. He died from multi-organ failure induced by an adult respiratory distress syndrome secondary to a systemic inflammatory response to the method used to deliver the new gene.
Initial public response to the tragic incident was rather mild, as it is understood that medical research is not without risks. But public perception of clinical gene therapy took a precipitous turn for the worse after the FDA cited the University of Pennsylvania investigators in December 1999 for multiple protocol violations in the trial. In addition, NIH revealed that only 6 percent of all serious adverse events observed in patients during past and current clinical gene transfer studies were reported to the NIH as required. These findings triggered a series of corrective actions by the relevant federal regulatory agencies including the FDA and the NIH, with the full cooperation and enthusiastic support of the American Society of Gene Therapy (ASGT). The Board of Directors of ASGT has accordingly adopted a policy that calls for all of its members to rigorously adhere to federal regulations and institutional guidelines in clinical gene transfer studies. This policy was published in the January issue of Molecular Therapy, the official scientific journal of the Society.
Another revelation that further shook the public's confidence in clinical gene transfer studies at its roots was that some investigators apparently have significant financial interests in the outcome of the clinical research they are conducting. To ensure the public that clinical gene transfer research will be performed with high ethical standards and without financial conflicts in the future, the ASGT Board of Directors adopted a second policy published in the May issue of Molecular Therapy. It prohibits investigators and team members from direct participation in the recruitment and clinical management of trial patients or in gaining participants' informed consent if they have financial interests in companies sponsoring the trial.
While the recent advances in clinical gene transfer to treat Hemophilia B and X-linked SCID show that gene therapy is indeed an immensely powerful technology that can be developed into novel treatments for a wide variety of human diseases, it is critically important for the scientific community to rise to the occasion and restore full confidence in the public's mind that clinical gene transfer research will be conducted by investigators in a responsible manner and free from financial conflicts. Only then can the full potential of using genes as medicines to treat human disease be realized, which will have a major impact on medicine and health in the 21st century.
Savio L.C. Woo, Ph.D., is the director of the Institute for Gene Therapy and Molecular Medicine at Mount Sinai School of Medicine in New York, where he is a professor, and is the immediate past president of the American Society of Gene Therapy.
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