Gene Therapy: Proceed with Caution

In 1983, when only three genetic diseases could be detected effectively by screening tests and scientists knew very little about how genes were controlled, Technology Review argued that anticipated clinical trials of gene therapy would need to follow stringent guidelines, given the technology’s previous failures. As ­Horace Freeland Judson explains in this issue (see “The Glimmering Promise of Gene Therapy”), not much has changed. Caught up in the promise of curing debilitating, life-shortening diseases by giving patients good copies of defective genes–and, it seems, eager for the glory of being the first to make gene therapy work in humans–some gene-therapy researchers have conducted sloppy, and even fatal, human trials in the intervening two decades.

Judson suggests that moving gene therapy forward will require well-­regulated scientific “drudgery.” In April 1983, Tabitha M. ­Powledge suggested a similar route in her article “Gene Therapy: Will It Work?” Though she wrote two years before it was possible to mass-produce genes through the process called polymerase chain reaction (PCR) and seven years before the Human Genome Project had officially begun, the challenges she laid out sound familiar–as does the promise of gene therapy.

First, as Bob Williamson of St. Mary’s Hospital Medical School at the University of London has pointed out, there are more than 2,000 single-gene disorders, and they are so diverse that most will require unique and idiosyncratic therapies. Furthermore, many are so rare that the benefits of gene therapy, if it can be achieved, may not warrant the expense, Williamson says.

Moreover, gene therapy is possible only for diseases for which the defective gene and its normal counterpart have been identified. Ways must still be found to copy normal genes in the laboratory so there will be enough to genetically manipulate and administer.

In addition, the inserted gene must function properly once inside the cell and direct the production of its normal product in amounts sufficient to cure the disease without harming the patient. This final step requires detailed knowledge of how genes manufacture proteins and what turns them on and off–knowledge that is likely to be some time in coming.

Even when researchers have developed a therapy for a particular disease, clinical trials in humans can begin only after extensive trials in animals. All these criteria are likely to be observed stringently, particularly because previous attempts at gene therapy have been unsuccessful and highly controversial.

Finally, gene therapy may turn out to be applicable only to genetic disorders caused by a single defective gene, and only to some of those, ­Williamson points out. The technique offers no way of dealing with abnormalities of entire chromosomes, nor is it likely to be useful for the most important group of diseases–such as diabetes, heart and circulatory diseases, and many mental disorders–in which both genes and environment play a role.

In short, while the first successful gene therapy will probably burst upon the medical world before long, many scientists are pessimistic. “The correction of a disease by gene therapy will be worthwhile only if there is no other simpler and more effective technique available,” Williamson says.

Baylor [College of Medicine]’s Thomas Caskey agrees that the uses of gene therapy will be limited. But he points out that many of the current treatments are unsatisfactory and do little more than ease the symptoms of disease.