The notion of treating a disease by inserting a healthy gene in place of one that is malfunctioning or missing -- so-called gene therapy -- is intriguing, but far from simple. The understanding of genes and how they work presents unique challenges to investigators, who are also faced with pressure to meet public expectations about the genetic approach to therapy. At Memorial Sloan-Kettering, genetics investigators, led by Human Genetics Chairman Dr. Lucio Luzzatto, are prepared to meet these challenges. In 1990, researchers at the National Institutes of Health (NIH) launched the first gene- therapy study involving two young girls with an immunological deficiency. The youngsters received blood cells containing a normal gene (which they lacked) that directed the body to produce a vital enzyme required for immunity. And so the era of gene therapy began. This study and others since then have been highly publicized -- and, indeed, sometimes exaggerated -- leading the public to believe that gene therapy is already established. Today the two girls are doing well. But since they've also been receiving the conventional medication used to treat their disorder, it isn't clear whether the gene therapy is working. More than 100 gene-therapy trials have been initiated since that first study. Cancer, a disease which results from a series of genetic alterations that lead to uncontrolled cell growth, has been a particular focus. But in reality, no studies have successfully used gene therapy to treat patients. "People had certain expectations about gene therapy, but they were confusing it with gene transfer," explained Dr. Luzzatto. Gene transfer is the technique by which a gene is inserted from one cell into the genetic material of another cell. Gene therapy takes it one step further: it is the use of gene transfer to treat disease in patients. Many purported gene-therapy trials conducted thus far were actually studies of gene transfer, in which scientists were inserting genes into cells in the laboratory, either to find out where they landed or to make sure they were not doing any harm. "Some scientists referred to their work as gene therapy, and that was premature," added Dr. Luzzatto. Gene transfer requires more than simply inserting a new gene into a cell. "In genetics research, we encounter hurdles that require us to develop and apply entirely new technologies," Dr. Luzzatto said. "So it is difficult to predict when we will be able to use gene therapy successfully to treat disease, although we are under enormous pressure to do so." A transferred gene must actually function, or be "expressed," once it has found its new home in its target cells. And cells receiving the gene must be able to divide and pass on the gene to new cells. Moreover, in the human body, the immune system may reject the new gene, recognizing it as a foreign invader. These are some of the formidable obstacles that geneticists, including those at MSK, must face. Last year NIH Director Dr. Harold P. Varmus appointed an ad hoc committee to assess the status and promise of gene therapy. Among other matters, the committee concluded that "overselling of the results of laboratory and clinical studies by investigators and their sponsors...has led to the mistaken and widespread perception that gene therapy is further developed and more successful than it actually is." The NIH committee cited the potential of gene therapy, but recommended a greater focus on the basic aspects of gene transfer and gene expression, and more research dealing with the fundamental mechanisms of disease development. And that is exactly what Dr. Luzzatto and his fellow researchers have been doing. Gene transfer may also be highly useful as an adjunct to cancer therapy. For example, MSK geneticist Dr. Michel Sadelain is trying to insert genes into bone marrow cells and T lymphocytes (a type of white blood cell) to reduce the risk of graft-vs.-host disease -- a common and potentially dangerous side effect of bone marrow transplants in which the transplanted marrow "rejects" the patient's tissues. "The notion that one could turn a cancer cell into a normal cell is still very ambitious," Dr. Luzzatto said. "But there are numerous ways in which one might be able to use gene transfer to make existing cancer treatments more effective."
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