Gene Therapy Moves Toward the Mainstream


When two infants received gene therapy in California last weekend, doctors were making a dramatic attempt to create working immune systems that nature was obligated to provide but didn't.

The newborns inherited a rare fatal immune disorder. They carried two copies of a defective gene for the enzyme adenosine deaminase (ADA) that is crucial for the immune system to fight infections. To correct their condition, doctors extracted from the umbilical cord blood stem cells that give rise to all blood cells, then placed them in a nurturing culture with genetically-altered viruses containing normal ADA genes.

Cells don't recognize genes, so genes can't get inside the cells on their own. They need to slip inside in a Trojan horse. The Trojan horse was the virus, genetically crippled so that it wouldn't harm the human host yet would maintain its ability to sneak inside cells. Tucked inside these viral vessels, the normal ADA genes were expected to enter the stem cells. Afterward, the stem cells (that now, doctors hoped, contained the healthy gene) were injected into the babies.

This is what is known as gene therapy. And gene therapy has come a long way, babies.

The two California infants brought to 114 the number of people who have had genes inserted inside their bodies either as therapy or as "markers" for progression of disease and treatments, according to records kept by the National Institutes of Health. Four years ago last week, the first gene marker was placed in a patient. And only three years ago, the first human received gene therapy.

She was a four-year-old girl who, like the two California infants, was born with defective ADA genes, and, therefore, no immune system. Doctors at NIH made medical history in 1990 by treating her and in 1991 by treating a nine-year-old girl with the same disorder by putting healthy ADA cells into the girls' T-lymphocyte blood cells, which are the white blood cells responsible for immune system protection. But T-lymphocytes do not live forever as do blood stem cells. And so, the treatment has had to be repeated.

The girls' immune systems improved significantly, according to Dr. R. Michael Blaese, chief of the National Cancer Institute's Cellular Immunology Section, who was involved with the girls' early treatment and with the stem cell gene therapy of the infants and the two girls. Although the girls have been going to school and doing well, last year Dr. Blaese told the Recombinant DNA Advisory Committee of NIH and the Food and Drug Administration, which authorizes all gene therapy experiments, that they may have "holes" in their immune system.

And so, while the two infants received most of the media attention last week, the girl initially treated in 1991, who is now 11 years old, also received stem cell gene therapy last week at NIH. This summer, the first girl treated, now six, will get similar treatment in hopes of making her immune protection complete.

Dr. Blaese and many other scientists involved in pioneering gene therapy said in interviews last week that they are very excited and hopeful about its future. "We all think it's going to revolutionize the practice of medicine," Dr. Blaese said.

Various forms of gene therapy are now being tried or are about to be tested on an assortment of diseases, including immunodeficiency disease, cystic fibrosis, melanoma and renal cell cancer.

And researchers predict that gene therapy will eventually be available for diseases from AIDS to cancer to diabetes.

There are signs that gene therapy already is knocking on the door of mainstream medicine. Just last month, the Johns Hopkins Medical Institutions applied for a $1.3 million five-year federal grant to open a gene therapy center. Dr. Frank Oski, chairman of pediatrics, said the center could be opening in six months, if funded.

A number of major medical institutions will likely open gene therapy centers eventually, Dr. Oski said. "It's an idea that everyone is talking about." But, he said, he doesn't think more than one is needed in a major population region.

The Hopkins center would initially treat cystic fibrosis, said Dr. William Guggino, who applied for the NIH grant for the Hopkins center. Initially only a few patients a year could be treated. Hopkins regularly sees 280 patients a year with cystic fibrosis.

The center it would become the hub for gene therapy treatment for many other diseases, he said. The Johns Hopkins School of Medicine "just evaluated itself, and gene therapy is one of the new therapies Hopkins expects to use extensively in the next decade," Dr. Guggino said. He said Hopkins and will proceed with gene therapy for cystic fibrosis, whether or not it receives NIH funds for a gene therapy center.

NIH currently plans to fund five gene therapy centers in the nation. Another applicant for the grant money is the University of Pennsylvania Medical Center, which has already established an Institute for Human Gene Therapy. Dr. James M. Wilson, director of the institute, said last week he is trying to develop gene therapies "in all areas of disease."

The institute is already treating patients with gene therapy for cystic fibrosis and an inherited disorder that causes severe cholesterol buildup and heart disease.

Judging by the hordes of people who try to get included in gene therapy trials, doctors will not lack willing participants as more and more experimental studies get under way.

Many hundreds of patients with brain cancer have tried to gain entry into an experimental gene therapy trial for brain tumors at NIH. Only 20 patients will be accepted. Eight have been treated so far.

One of the eight is a physician who said last week he feels very lucky to have gotten into the trial. Dr. Michael White, 50, a project manager for the Agency for International Development, said that after his wife learned of the planned trial, he called NIH.

"They said they weren't taking anyone yet. They very much gave me a 'don't call us, we'll call you' kind of response," he said. "Surprisingly to me, within a month of being told that, I was called . . . and told there was a space available and I could be part of it. I was elated."

Pam White, his wife, said she anticipated that the NIH clinical center where her husband stayed more than a month would be filled with gloomy, depressed people. She said she was pleasantly surprised. "The staff is wonderful and very supportive. I talked to other patients and family -- they are so incredibly upbeat and positive. They've been given one more chance to find a solution."

Dr. Edward H. Oldfield and Dr. Zvi Ram, both of the National Institute for Neurological Disease and Stroke, and Dr. Kenneth Culver and Dr. Blaese of the National Cancer Institute, are in charge of the trial which began in February.

Dr. Oldfield said it is too early to say conclusively whether the tumors are responding to treatment. But he said all eight patients are still alive and none is worse.

The gene therapy "has the potential of curing primary brain cancer, but not metastasized brain cancer," Dr. Oldfield said. However, observers of the trial caution that many more steps still need to be worked out.

Dr. W. French Anderson, the pioneer of gene therapy who recently left NIH for the University of Southern California in Los Angeles, says the brain tumor trial is "the first major trial" for using gene therapy in cancer. The treatment relies on insertion of a gene into a patient's tumor that has the ability to act upon a certain drug, rendering it toxic enough to kill the tumor.

There will be many variations of gene therapy over the coming years, some continuing to use viruses as vessels to slip genes into targeted cells. But Dr. Wilson says that over the next five years scientists will also develop other strategies that do not use viruses because of concerns that "viruses are always capable of recombining with other viruses" and either causing uncontrollable infections in a patient or getting out into the environment as new life forms. So far, that has not happened, he adds.

Dr. Wilson said two new non-viral methods will be used in the next few years. In one, scientists will coat a gene with synthetic fat that fuses with the membrane of a targeted cell.

Another approach will attach the gene to a nutrient, so that the gene gets inside the cell by piggybacking onto the cell's food.

The excitement and expectation among well-known scientists and physicians involved in gene therapy is riding high. But excitement needs to be tempered with caution. There were, after all, well-known sports pundits who predicted at the opening of this baseball season that the Orioles would walk away with the championship.

If things can go wrong in baseball, they surely can go wrong in medicine, particularly during the rough trek across new medical frontiers.

There are four things that can be said with certainty about gene therapy today:

The first two girls to receive treatment have been helped by it, but it is too early to know the outcome for other patients.

Molecular biological techniques exist, and different ones will be developed over the next five years for altering a person's genetic makeup, with the possible outcome of controlling certain diseases.

The future of gene therapy will largely depend on individual researchers' abilities to figure out how to make it work.

And, as of May 23, 1993, this story about gene therapy has no ending.

Mary Knudson, a former Sun reporter, is a free-lance medical and science writer.

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