A new era of gene therapy

FDA Consumer, Dec, 1991 by Harold M. Schmeck, Jr.

For thousands of years people have been taking medicines by mouth and for a scant century by injection. Now an entirely different method is at hand--medication delivered by genes.

The name coined for this new concept is gene therapy. It seems so revolutionary that few people think of it as a new way of administering medicine, but that is one of the most important aims. Instead of giving drugs to the patient, the doctors modify some of the patient's own cells by inserting a gene that instructs those cells to manufacture an important substance. The transplanted genes have turned the patient's own cells into factories for making the medicine. It is then delivered continuously to the tissues that need it. There are limitations, of course. The medication has to be a natural substance that the gene-modified cell can manufacture. It wouldn't be useful for delivering aspirin, for example, or any drug that is a totally artificial chemical.

The list of potential products includes natural substances that have anti-cancer potential, such as tumor necrosis factor, or other gene products that could reduce the perils of heart disease by changing the balance of blood lipids. Researchers at the National Heart, Lung and Blood Institute are already planning to try gene therapy against hemophilia, hoping to protect patients against catastrophic bleeding by transferring normal genes for making substances that help the blood clot. Conversely, some powerful anti-clotting substances such as TPA (tissue plasminogen activator) could be delivered by the genetic route to patients under treatment for heart attack.

Scientists at the National Cancer Institute (NCI) hope to make genetic changes in pieces of a patient's cancer tissue so the tissue will spark a powerful cancer-destroying immune reaction when it is re-implanted in the patient's body. Scientists elsewhere are doing research that some day might make it possible to erase and replace a defective gene in specific tissues to correct a deadly inborn error.

Most of the applications of gene therapy will come into use only after the dawning of the 21st century, but that is less than a decade away and, in fact, human gene therapy has already begun.

PEG-ADA

The new era opened on Sept. 14, 1990, when a solemn little 4-year-old girl at the National Institutes of Health's Clinical Center in Bethesda, Md., began to receive a steady drip of fluid into a vein in her arm. That first treatment took only about a half hour, but preparation for it took decades and the implications were profound. (See accompanying article.)

In the milky fluid she received were about a billion of her own white blood cells treated previously in the laboratory to equip them with a foreign gene. The young patient lacked effective copies of that gene, and the lack doomed her to be continually hostage to all manner of chance infections. Most of these would be minor annoyances to most humans. To her, each infection was a threat of death.

The usual course of events for children with her disease is to die by the age of 2 or 3. For this little girl, a relatively new drug, PEG-ADA, is calling a truce with the disease and buying time for the test of gene therapy. The drug was approved by the Food and Drug Administration in 1990. The aim of her gene therapy is to give the child long-term health and the hope of a normal life. It is too soon to say how well it will work, but her doctors see hopeful signs.

"All of her immune functions appear to be improving. She is normal in some values. She is still not normal in others, but she is improving steadily," said W. French Anderson, M.D., of the National Heart, Lung and Blood Institute, the chief architect and guiding spirit of her gene therapy treatment. By values," he means such things as the number of various kinds of immune defense cells in her circulating blood. Anderson, who has spent much of his professional life at the institute, has dreamed and fought for the concept of gene therapy since he was an undergraduate in college 30 years ago. The idea was widely ridiculed in the early days, he says, but now it is fast becoming reality.

Correcting Genetic Disorders

The little girl suffers from a deadly genetic disorder called severe combined immune deficiency (SCID). Because of a tiny chemical error in her DNA--the genetic material--she lacks a properly functioning gene for making an enzyme called adenosine deaminase (ADA). Her particular type of severe failure of immunity is therefore called ADA deficiency. In the gene therapy treatments, some of her white blood cells are first removed and treated in the laboratory to install good copies of the ADA gene. Then the cells are put back into her circulating blood. As long as those gene-modified cells continue to function, they can provide the enzyme that she needs. How long will they function? That is one of the key questions yet to be answered.

Genes are chemical instruction sheets that living cells use to guide all manner of life processes. Most genes are the blueprints for making one or another protein vital to the body. Every human has an estimated 100,000 genes. A minor distortion in chemistry--a "spelling error"--in just one of those genes is responsible for the child's grave illness. It is an extraordinarily rare condition. Only about 10 ADA deficiency patients are known in North America. Without treatment, they would all die in infancy or early childhood.