"While current clinical studies look promising," she said, "the experience of the first decade of gene therapy, which began in 1990, has led researchers to temper their expectations of quick results. The practical problems of delivering therapeutic genes, efficiently producing clinical benefits, and avoiding toxic side effects have often disappointed researchers and patients with the disease, both of whom are hoping to find a cure or treatment."
Gene therapy is a novel form of disease treatment because the active agent is a sequence of DNA instead of the proteins or small molecules that are currently used as drugs, said Dr. High. Hemophilia is among the diseases that lend themselves more readily to gene therapy because even small increases in the clotting factor that is deficient in a patient’s blood can improve the disease from a severe form to a much milder form, and result in great improvements in quality of life for hemophilia sufferers.
Currently, patients with severe hemophilia receive frequent, intravenous infusions of manufactured engineered clotting factor. However, these treatments are expensive and inconvenient, and sometimes stimulate an immune reaction that neutralizes the benefits of treatment. Because a single defective gene causes hemophilia B, gene therapy involves inserting a normal version of the gene, which makes a normal protein—the clotting factor. (The two common forms of hemophilia are hemophilia A and hemophilia B. While symptoms of both forms are clinically identical for patients, hemophilia A affects clotting factor VIII, while hemophilia B affects factor IX.)
Dr. High’s involvement in gene therapy began with her earlier pioneering investigations of the genetics of hemophilia, including her studies in mice and dogs. The animals have served as well-understood models for studying hemophilia and possible gene therapies. "An advantage hemophilia has as a target for gene therapy," she added, "is that we can more thoroughly test the effectiveness of promising approaches in small and large animals before proceeding to human trials." In 1999, her team announced that gene therapy achieved long-term improvement of naturally occurring hemophilia in dogs. That work produced levels of clotting factor in the dogs that would be therapeutic if achieved in humans.
Dr. High’s approach uses a genetically engineered virus called adeno-associated virus (AAV) as a vector, or delivery vehicle, to carry genes into a patient’s cells. In partnership with Stanford University School of Medicine, Children’s Hospital carried out early-stage clinical trials in adult patients with hemophilia B. In those trials, the researchers showed in 2000 that the introduced gene induced patients’ cells to produce clotting factor IX, the blood-based protein that is highly deficient in patients with the severe form of the disease. There were no serious side effects of the treatment, which delivered the gene by direct injection into the patients’ leg and arm muscles.
Last year, The Children’s Hospital of Philadelphia and Stanford University, in conjunction with the biotechnology company Avigen, Inc., began clinical trials that infuse the gene therapy product directly to patients’ livers. Earlier animal studies by the teams at both hospitals suggested that a liver-directed approach, aided by improved genetic engineering of the gene package, could more efficiently produce clotting factor from a given amount of gene product. "Our goal is to determine if we can achieve the same therapeutic results for human patients that we found in hemophilic dogs," she said.
The path of the hemophilia clinical research has not been free of obstacles. The liver-directed gene therapy trials were halted briefly when portions of the AAV vector were found in a patient’s semen. This result did not persist beyond a few weeks, and new safety studies indicated that gene transfer probably does not occur in the sperm cells. Gene therapy researchers must strictly avoid altering the DNA of germ line cells, such as sperm, to avoid the potential of transferring unknown effects to a patient’s children. In response to the safety studies, the U.S. Food and Drug Administration permitted the liver-directed clinical trial to resume in December 2001.
Both of the hemophilia B gene therapy clinical trials have been collaborations among Dr. High, geneticist Mark Kay, M.D., Ph.D., of Stanford University School of Medicine and Avigen, Inc., which is based in Alameda, Cal. Catherine S. Manno, M.D., is the principal investigator of the trials at Children’s Hospital, while Bert Glader, M.D., Ph.D. is the principal investigator at Stanford.
The hemophilia gene therapy trials have been closely watched because they may represent a milestone in genetic-based medicine, with implications for many other genetic and acquired diseases. Dr. High adds that only 20 years ago, drugs based on recombinant technology, such as insulin, growth hormone and clotting factors, seemed a daunting challenge for medical researchers, but are now standard weapons in physicians’ toolboxes. "Advances in research and technology suggest that gene therapy will also become a successful and powerful method for treating human disease," she added.
Founded in 1855 as the nation's first pediatric hospital, The Children’s Hospital of Philadelphia is ranked today as the best pediatric hospital in the nation by a comprehensive Child Magazine survey. Its pediatric research program is among the largest in the country, ranking second in National Institutes of Health funding.
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