Gene Therapy | Introduction
Gene therapy is based on the concept that genetic disorders and acquired diseases can be treated by replacing abnormal or absent genes or by modifying their functions. Inherited disorders such as cystic fibrosis and hemophilia, as well as catastrophic diseases such as cancer and AIDS, are prospective candidates for gene therapy. Although cures for these ailments would be welcome, some medical researchers suggest that the range of diseases that can be treated with gene therapy may be limited. According to research scientist Lynn Elwell, “Only a handful of the many diseases that have a genetic basis are amenable to treatment via gene therapy: Genetic disorders caused by single genes.” She also adds that “chromosomal disorders, such as Down syndrome, cannot be cured by gene therapy, nor can disorders resulting from complex interactions between many genes or between genes and environmental factors.” Advocates of gene therapy contend that this form of treatment offers hope to the thousands of people whose diseases cannot be cured through current medical means. In 2000, researchers used gene therapy techniques to help mice with hemophilia produce high levels of the protein needed to restore and maintain the clotting property of blood. For advocates, knocking out this disease in the human population makes gene therapy—despite its limitations— a worthwhile pursuit.
Gene therapy is composed of two categories: somatic gene therapy and germ line gene therapy. In somatic gene therapy, therapeutic genes are introduced to the diseased cells of a patient in hopes that they will genetically alter them to function normally. In germ line gene therapy, therapeutic genes are introduced to reproductive cells (egg and sperm cells) to prevent the manifestation of a genetic disorder before the patient is born. This approach would alter the patient’s genetic makeup and the genes he or she passes on to succeeding generations. Additionally, therapeutic genes can be introduced to cells in several ways. In ex vivo gene therapy, a patient’s blood or bone marrow cells are removed and cultivated in a laboratory, exposed to a virus carrying therapeutic genes, and returned to the patient. In in vivo gene therapy, a virus or other particle carrying genes is inserted directly into the patient’s body. The particle that carries genes to cells is known as a vector. Usually modified viruses are used as vectors in clinical trials, but the use of nonviral vectors, such as liposomes (microscopic fatty particles), are also under investigation. When genetic material is inserted without a vector, it is known as naked DNA.
The first human gene therapy clinical trial occurred in 1990, in which Ashanti DeSilva, then four years old, was treated for adenosine deaminase (ADA) deficiency, a rare genetic disorder that severely limits the functions of the immune system. Today, she leads a normal life and receives weekly injections of synthetic DNA to maintain her immune system. Some researchers herald the outcome of DeSilva’s clinical trial as gene therapy’s first success story, spurring interest and support for gene therapy research in the 1990s. However, hundreds of unsuccessful gene therapy clinical trials followed thereafter, dimming the initial optimism. But it was the death of a young patient that subjected gene therapy research to intense scrutiny. On September 17, 1999, eighteen-year-old Jesse Gelsinger died during a gene therapy clinical trial for ornithine transcarbamylase (OTC) deficiency, a rare metabolic disorder that is marked by dangerous levels of ammonia in the bloodstream. Although his condition was nonfatal and was controlled by a strict diet and regimen of drugs, Gelsinger volunteered to participate in an experimental treatment for a deadly type of OTC deficiency in babies at the University of Pennsylvania. He died after a vector injected into his liver triggered an immune response that led to multiple organ failure. The vector used to deliver therapeutic genes was a modified cold virus.
Immediately after Gelsinger’s death, the Food and Drug Administration (FDA) froze all gene therapy clinical trials at the University of Pennsylvania and those under way at several other institutions. In addition, the prodecure of informed consent for clinical trial volunteers at the University of Pennsylvania was under fire. Some criticized the university for not thoroughly advising Gelsinger of the risks associated with the experiment in which he participated. Furthermore, an inquiry conducted by the National Institutes of Health (NIH) alleged that more than 650 adverse reactions in gene therapy trials were not immediately reported. In response, the FDA and the NIH took several steps to toughen the regulation of federally funded gene therapy research. They launched two initiatives in March 2000—the Gene Therapy Clinical Trial Monitoring Plan and the Gene Transfer Safety Symposia—to strengthen the oversight of gene therapy clinical trials and foster communication between gene therapy researchers. The FDA also conducted random investigations of seventy gene therapy clinical trials across the United States. Moreover, legislation to impose monetary penalties for the violation of clinical trial requirements (up to $250,000 per researcher and $1 million per institution) was drafted the same year. As of December 2003, such legislation had not been passed by Congress.
Proponents believe that increased regulation of gene therapy research is beneficial because it protects the safety of patients who volunteer for gene therapy clinical trials. According to Faith Lagay, a senior research associate at the American Medical Association, “We must better train (and perhaps certify) investigators to select, inform, and protect subjects in clinical trials” because “gene therapy illuminate[s] the weaknesses and cracks in our ability to monitor and enforce procedures for protecting human subjects and preventing their exploitation for science or commerce.” Kathryn Zoon, director of the FDA’s Center for Biologics Evaluation and Research, adds that monetary penalties “will give added assurances” to gene therapy patients that researchers and institutions are adhering to gene therapy research guidelines.
However, detractors of applying more restrictions to gene therapy research argue that it will needlessly delay its progress. Some assert that gene therapy is unfairly being singled out because other types of clinical trials expose their subjects to similar risks. The late Laura Raines, senior vice president of the Genzyme Corporation, a biotechnology company, claimed that “creating special rules exclusively for gene therapy research risks stigmatizing a product class for which the risks appear to be comparable to other types of products.” Additionally, regarding the use of monetary penalties for regulation, Pamela Zeitlin, associate director of the Pediatric General Clinical Research Center at Johns Hopkins Hospital, suggests that they “would be very discouraging” for young researchers who contemplate joining gene therapy research, a field that urgently needs new recruits.
As of December 2003, gene therapy treatments are still experimental and have not yet been approved for any clinical use by the FDA. Although research pushed on after the tragic death of Jesse Gelsinger, the controversy surrounding it has not abated. In 2003 the field suffered another setback: Two French boys who were successfully treated for severe combined immunodeficiency in gene therapy clinical trials developed leukemia as a result of their treatment. In At Issue: Gene Therapy, the authors explore the benefits and risks involved in this young field of research as well as the significant implications gene therapy will have on human health if it becomes an acceptable form of treatment.
