Gene Therapy

B

Chimeraplasty

Some researchers believe that in the near future a process called chimeraplasty may make it possible to fix defective genes within a cell directly, making it unnecessary to insert new genes into cells. Researchers have developed short segments of DNA called oligomers, whose nucleotide sequences complement those of a gene in which a defect occurs. When inserted into the cell's nucleus, oligomers bind to the defective gene where the sequences are correct, but they do not bind properly at defective sites. The cell's repair machinery sees this “bump” in the DNA and interprets it as a signal to repair the defective gene. Chimeraplasty has been successfully tested in animals, and investigators have recently begun to test it in humans.

C

Clinical Trials

Once gene therapy methods have been developed in a laboratory and tested on animals, scientists need to prove that they work in humans. Scientists approach any experiments in humans with great care. Since gene therapy is a new technique that may have unforeseen risks, they develop a proposed experiment, known as a protocol, that incorporates strict safety guidelines.

In the United States, a gene therapy protocol must be reviewed and approved by the Recombinant DNA Advisory Committee of the National Institutes of Health (NIH). If approved, the protocol is then submitted to the Food and Drug Administration (FDA) for approval. After the FDA gives permission for human testing to begin, they continue to monitor the experiments. In the course of a clinical trial, researchers are required to report any harmful side effects resulting from the gene therapy treatment under study. The FDA has approved more than 400 clinical trials of gene therapy, although in early 2003 the FDA placed a temporary ban on 30 of the clinical trials that used retrovirus vectors. The FDA took this precautionary measure after the French gene therapy trial for SCID resulted in a life-threatening disorder that may have been caused by the procedure. The FDA expects to permit the U.S. trials to resume if safety measures are taken to minimize the risk of using retrovirus vectors.

V

Debates about Gene Therapy

Most scientists are confident that technical problems associated with gene therapy will eventually be overcome, allowing its use by a much larger number of people. That prospect has prompted ethical and moral concerns about gene therapy, especially regarding alterations to germ cells.

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Critics and proponents all agree that the risks of gene therapy must not be substantially larger than the potential benefits. For this reason, most of the early gene therapy experiments have been on rare diseases that can cause intense suffering and for which no treatment exists. Initial experiments using gene therapy in the treatment of cancer and AIDS have been conducted primarily in patients for whom all other treatments have failed and who are near death, so the risks are small. This is the same procedure used to test new drugs against these diseases. But many people feel that because gene therapies use altered genes and potentially dangerous viruses, these treatments should be more extensively tested than drugs before being approved.

Critics have charged, for example, that the health risks exceeded the benefits in a case in 1999 that resulted in the first death linked to gene therapy. In that case, an 18-year-old Arizona man received gene therapy for a rare genetic metabolic disorder called ornithine transcarbamylase deficiency. He died from failure of his liver and other internal organs four days after researchers at the University of Pennsylvania in Philadelphia infused a genetically modified adenovirus into his liver to correct the defect. Many observers believe the man should not have been treated because he had a mild form of the disease and drugs and diet may have been able to control his symptoms.

The potential risks are also at the center of the more contentious debate about germ-line therapy. Although the potential benefits of success are great—lifelong freedom from genetic disease and the elimination of dangerous genetic legacies in families—the risks are also much greater. For example, partial correction of a genetic defect might lead to the birth of a severely deformed child. Without the intervention of gene therapy, such a pregnancy might otherwise result in a miscarriage. The procedure might also bring unforeseen harm to the mother, through either unpredicted spread of the virus vector or other problems associated with the procedure.

Beyond scientific and medical risks, germ-line therapy opens thorny moral dilemmas. Critics argue that, for example, people do not have the right to sculpt the genetic blueprint of children—a decision in which the child has no voice. Others portray the experiments as the first step down the slippery slope to designer babies. Critics fear that before too long, any child who has not received enhancement through gene therapy and who does not measure up to some arbitrary standard of health, behavior, or physique will be seen as flawed.

Few researchers endorse genetic enhancement of babies, and most think it is a bad idea. For one thing, enhancement is a much more complex procedure than repairing a genetic defect. Such apparently simple traits as blue eyes or brown hair are caused by complex interactions among genes. Interfering with that interaction is likely to have unexpected consequences, increasing the risks for health problems. Nevertheless, the concept of enhancement received a boost from studies showing that mice can be made more intelligent by adding a single gene to their genome and that they can be made more sociable by adding a different gene—apparently, in both cases, without adverse effects.

VI

Challenges for Gene Therapy

Gene therapy is a powerful new technology, but many advances are necessary before it will make a noticeable impact on the treatment of disease. Researchers must make vectors that are more effective at invading large numbers of cells, must find new ways to manufacture the vectors in large quantities, and must produce better promoters so that larger quantities of proteins are produced.

Observers note that the field of gene therapy is still very young and the rules governing gene therapy clinical trials are evolving as the field evolves. As a consequence, some safety issues have not been fully addressed, which critics charge may have resulted in the unnecessary death in the gene therapy clinical trial in 1999. That death provoked a detailed review of the methods used in gene therapy trials, and the NIH and FDA developed plans for increased oversight of safety and efficacy in gene therapy trials.

Despite some technical setbacks in the methods used in gene therapy and some procedural problems in testing gene therapy in humans, most experts believe that use of gene therapy in medicine is inevitable. Experts believe that within the next few decades, doctors will routinely correct simple genetic defects, eliminating a number of diseases that now plague humankind.