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Gene Therapy

Investigators have been searching for ways to add corrective genes to cells harboring defective genes. A better strategy might be to correct the defects

Eric Kmiec

This article was published in the May-June 1999 issue of American Scientist.

In the middle of the 19th century, the now-famous monk Gregor Mendel performed his landmark experiments indicating that certain traits can be inherited, and he postulated a discrete unit of inheritance that we now call a gene. Since then, scientists have come to appreciate how much of an individual's constitution is determined by genes, and, in particular, they have focused on the link between genes and disease. Indeed, over the past 10 or so years, identifying disease-related genes has become something of a cottage industry within the scientific community.

Any reader of newspapers knows just how fruitful this enterprise has been. Almost daily come reports about the discovery of a new gene that contributes to some disease or another, be it sickle cell disease, muscular dystrophy, familial hypercholesterolemia, Alzheimer's or some form of cancer. Right now, therapies directed toward these conditions can only alleviate the symptoms—the manifestations of the defective genes. Implicit, and sometimes explicit, in stories about genetic discoveries is the idea that new therapies can be created that directly address the source of the problem. These gene therapies seek treatments, even cures, that act at the level of the gene itself.

Most of the gene therapy techniques developed so far are of the gene-addition variety; that is, they attempt to provide a good copy of a gene to a cell that harbors a bad one. The hope is that the good, corrective gene will compensate for the bad one and restore the cell to its proper function. Gene addition has been achieved by a variety of means—not only in test-tube experiments, but in clinical trials involving real patients as well. Yet, to date, the results of these trials have been disappointing. Even the most successful clinical trial has fallen short of therapeutic efficacy.

The professor emerges from the goofy booth . . .Click to Enlarge Image

Unfortunately, many of these trials have been widely publicized—and, in some cases, oversold—in popular books and magazine articles. Having failed to live up to the inflated expectations created by such publicity, these disappointing trial results have left a general impression that gene therapy cannot now or ever fulfill its initial promise. But these clinical trials may have been conducted before the technology was fully mature, driven in part by investor demands on biotechnology companies to rush products to market. Such clinical trials were almost certainly destined to fall short of the mark.

Many of the fundamental problems with gene therapies have not yet been worked out sufficiently to make the technology therapeutically viable. A number of vehicles have been developed to deliver corrective genes into cells. Some are more effective than others, but none is yet exactly right. The greater challenge, however, lies in the problem of how to make the therapeutic gene behave reliably and at clinically beneficial levels.

Making gene therapy a successful endeavor will require careful research to understand why traditional approaches have not produced the hoped-for results and, in turn, to improve them, while exploring new ways to deal with genetic defects. In my own laboratory, we are considering the possibility that inserting an entire gene into a cell and then expecting it to behave as a native gene may be overly ambitious at this point. It may also be unnecessary. Since the defects in many disease-related genes are fairly small, my colleagues and I are exploring ways to repair rather than replace them. Our initial results lead us to be cautiously optimistic that with adequate basic research this or some other approach will ultimately yield fruit. My own feeling is that pronouncements of gene therapy's imminent demise are as premature as were those overly optimistic pronouncements of its imminent success. At its core, the notion of gene therapy or gene correction is scientifically sound.

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