The ability to replace defective genes with healthy ones within the human body has long been a goal of genetic therapists. The concept is a simple one, in principle, involving piggybacking a healthy gene onto a virus that then carries it into the cell’s nucleus where it becomes integrated into the DNA.

Once established in sufficient quantities, the expectation is that the healthy gene will take over the function that the body’s defective gene cannot perform. In fact, the procedure seemed so certain of immediate success that one leading researcher, Mark Kay of Stanford University, recalls, “I figured by the time I’d finished medical school and my residency, all the interesting diseases would already be cured.”

The reality, as Trisha Gura makes clear in the March 2 issue of Science, is quite different. She uses the collaborative research of Kay, and Katherine High of Philadelphia’s Children Hospital, on a cure for hemophilia to illustrate the pitfalls of research in gene therapy.

Hemophilia is a genetic disease linked to the X chromosome that affects roughly 1 in 5,000 people, almost all males. The disease is characterized by the body’s failure to produce one or more enzymes or clotting factors that aid in blood clotting. People who produce less than 1 percent of any of the clotting factors suffer from uncontrollable bleeding episodes and severe joint damage. In order to be beneficial, enough healthy genes would have to be incorporated into the patient’s DNA to reach or exceed that 1-percent level. However, the first viral vectors used to carry the genes into the cell often caused a severe immune response in the patient. Nonetheless, gene therapy was quickly gaining credibility, particularly when a new vector called AAV was found that could avoid detection by the body’s immune system and did not appear to provoke the same potentially dangerous response.

In 1998, High led a research team that injected AAV combined with one of the human clotting factors into mice that had been genetically altered to have hemophilia. The procedure was successful as was one a year later when the disease was partially cured in dogs using AAV in combination with canine clotting factor. Independently, Kay had done the same experiments, and their reports appeared together in the same issue of Nature Medicine. The difference was that High injected muscle with the combination while Kay pumped it directly into veins leading to the liver. Both produced the desired 1 percent increase in clotting factor, and Kay’s procedure required less of the gene-vector combination. The liver procedure is riskier than injecting into the muscle, and this point became suddenly important when the two began a collaboration involving human subjects.

In 1999, High and Kay obtained approval to inject three hemophilia patients with their gene-vector combination. The test was to study safety, not effect a cure, and it worked better than they dared hope. Not only was there no harm to the patients, but they showed signs of alleviating disease symptoms. One even bettered the benchmark 1 percent increase in clotting factor.

Bolstered by this success, new tests were planned, but, before they could start a second trial, the unthinkable happened. A young man died in an unrelated gene therapy trial at the University of Pennsylvania’s Institute for Human Gene Therapy. He died from a massive immune response after a gene-vector unit was injected into his liver. Although the gene produces liver enzymes and not clotting factor, the fact that it was injected directly into the liver, the same method used by Kay, caused the pair to immediately halt their work and review all their animal and human data. They were only too well aware of the fact that, while not directly involved, the entire gene therapy community was now under intense scrutiny.

Finally, High and Kay decided to continue with her technique of muscle injections while holding off on direct liver administration. Also, they have opted for a patient-consent form that fully explains all of the risks involved including possible death. So far, their trials have been modestly successful and will soon be complicated by a series of new guidelines being put in place by various federal agencies. In spite of these setbacks, pharmaceutical companies, including Germany’s giant Bayer Corp., are investing millions of dollars into the hemophilia trials. It is a bittersweet time for High and Kay who are just beginning to see their research go forward while under a public relations microscope.

“It’s a highly visible field,” said High in the Science article, “because of public, commercial and political interest. That creates a great deal of pressure.” Nonetheless, she is optimistic that there is tremendous potential for gene therapy across the entire field of medicine.

Clair Wood taught physics and chemistry for more than a decade at Eastern Maine Technical College in Bangor.