A Thriving Pioneer of Gene Tests

”. . . A great day for the world. A great day for medicine. Gene therapy has been approved. Our daughter is the first patient in the world to receive it.”

Those were the words that a tired but exhilarated Van DeSilva penned into her personal journal on the evening of Sept. 14, 1990. Her 4-year-old daughter, suffering from an extremely rare and fatal disease that cripples the immune system, had just made medical history.

Ten days earlier, at the National Institutes of Health in Bethesda, Md., Ashanthi DeSilva sat quietly watching the children’s adventure fantasy movie “Willow” as researchers repeatedly drew blood from her tiny arm. They extracted white blood cells from the samples, then transferred those into tissue culture in the lab. As the cells grew from tens of millions to billions, scientists added a corrected cell that--it was hoped--would do the work that her own flawed genes could not.

On the day that her mother wrote those uplifting words, Ashanthi was injected with the cells containing the healthy genetic message. The daring experiment in gene therapy had seemingly gone well and scientists celebrated their arrival on the cutting edge of a new medical frontier.

Today, Ashi, as she is known, is a thriving teenager in Ohio, a 13-year-old who gets all A’s and Bs, plays the piano and basketball and rarely gets a cold.

She is not cured: Ashanthi still must take a drug that helps keep her disorder under control. But her body produces some cells with the new gene and is faring better than scientists had dared imagine 10 years ago.

Gene therapy, however, is under siege. Federal agencies have begun to crack down on experiments, after the unexpected death of a man who was not fatally ill when his gene therapy began. Scientists and government officials have expressed skepticism about cases like Ashi’s, arguing that anecdotes do not constitute proof. And the public has grown weary of New Age medicine, worried that the early promise of high-tech science has given way to unacceptable risks.

Now, scientists again look to Ashi to validate their case.

Sometime this summer, doctors again will take blood samples from her, again grow them in the lab and again genetically change the cells and return them to her body.

But this time the corrected cells will be stem cells--the purest kind. This time, researchers will transplant them into her bone marrow, hoping that the marrow, from then on, will stop producing the genetically defective cells and only produce those that are genetically perfect.

And this time, they hope that they finally will have their proof.

Dr. R. Michael Blaese, the former NIH researcher who treated Ashi in 1990 and is designing the new, more advanced therapy she will receive soon, is baffled by the current furor over gene therapy. He believes that, without the therapy she received, Ashi likely would have died in childhood from her disorder, which left her vulnerable to one infection after another.

While her body is still making cells with the bad genes, many of the good genes inserted years ago are still circulating in her system, helping to keep her healthy, he said. He thinks that the public is holding gene therapy research to an unrealistically high standard.

“This field was supposed to be magic. And people think that, if you don’t reach a high level of expectation, you are a failure,” he said.

Success Measured in Increments

“The reality is that success often

comes in increments. Something may be of value, even if it’s not a cure. To say that gene therapy has never helped anyone is simply false.”

The original rationale behind gene therapy was to treat genetic diseases by replacing a non-functioning or defective gene, which was the case with Ashi. While gene therapy experiments still focus on genetic disorders, the field has broadened considerably in recent years to look at gene therapy approaches to a range of other diseases, among them cancer, heart disease and AIDS.

Since 1990, 4,000 patients have participated in 378 gene therapy trials, of which 343 are still underway. There are 32 gene therapy trials ongoing in California, according to federal health officials. Some of the sites in Southern California are UCLA, City of Hope National Medical Center in Duarte, Cedars-Sinai Medical Center, Scripps Clinic in La Jolla, USC, Childrens Hospital Los Angeles and Sidney Kimmel Cancer Center in San Diego.

Gene therapy research became controversial after 18-year-old Jesse Gelsinger of Arizona died in September after receiving experimental gene therapy for a liver disorder at the University of Pennsylvania’s Institute of Gene Therapy.

Since his death, federal health officials determined that the institute violated federal regulations in the conduct of the study. They halted all gene therapy there and began to tighten oversight on all researchers doing gene therapy experiments.

For Ashanthi’s coming experiment, her doctors--as they are required to do--sought and received permission from the Food and Drug Administration months ago. And they also won the blessings of an NIH advisory panel that oversees gene therapy research. Approval by the Recombinant DNA Advisory Panel is no longer required as it was in the early days of gene therapy. But the panel has the right to request a review, and it did, likely because “of the current climate,” Blaese says.

Federal health officials acknowledge that the field has produced some encouraging results, recent among them reports on treating hemophilia and in bypassing clogged coronary and leg arteries.

But, overall, until there is definitive scientific proof, they tend to dismiss many such cases as anecdotal.

‘Hints of Success’

“We do have some hints of success, but those are anecdotal studies,” said Lana Skirboll, NIH’s director of science policy, who is one of the officials in charge of her agency’s investigation of gene therapy practices.

“The scientific community is hesitant to talk about successes without peer review and duplication,” she added.

Usually, however, science requires carefully designed clinical trials with “controls” for comparison purposes and large numbers of volunteers so that statistically significant differences can be documented.

But highly experimental gene therapy has been tested for the most part only on small numbers of very ill people, who often have died from disease--making it difficult to prove success.

In 1993, for example, Blaese conducted a gene therapy trial on 15 patients with glioblastoma, a deadly brain cancer. There were no controls. All of the patients were very ill and had failed conventional therapy.

All 15 received experimental gene therapy. They were given a gene designed to change the metabolism of the cancer cells, making them resemble a herpes virus, so they would be vulnerable to the antiviral drug acyclovir. The hope was that cells treated with the gene would be killed by the drug.

Fourteen died, victims of their brain cancers. One man, however, is alive and cancer-free seven years later. Gene therapy was a last resort for a dying man--he had had surgery, chemotherapy and radiation, all of which had failed. The cancer had returned in three separate sites.

Would he have died without gene therapy? Blaese thinks so but he cannot prove it.

“He had a bad brain tumor and it came back. He had gene therapy and it went away,” said Blaese, who now conducts genetic research for a private company, Kimeragen Inc. in Newtown, Pa., but still serves as an NIH consultant.

“It’s very difficult to say with certainty that the gene therapy cured him. He might have been luckier than hell to respond when others didn’t. It wasn’t a controlled clinical trial, so the scientific community dismissed it as unproven,” Blaese said.

“One anecdotal case of a ‘cure’ gets no attention,” he added. “But those same people who dismiss it will jump on a single anecdotal case of a terrible side effect, or death, and paint the entire field with a broad brush. And that’s very frustrating.”

Ashanthi’s parents, originally from Sri Lanka and now living in North Olmsted, a suburb of Cleveland, are saddened that Gelsinger’s death has thrown pessimism over a field they believed saved their daughter.

“I feel very sorry for Jesse’s family,” said Van DeSilva, a homemaker whose husband, Raj, works as a chemical engineer. “A child is dead and that is so very sad. My heart is broken for his parents. I’m sure his mom and dad feel a lot of pain.

“But what am I going to say? I cannot say anything bad about gene therapy. It worked for us,” she added. “In my heart, my little girl was cured that day--and the part of my heart that belonged to her was healed too.”

Ashi became ill soon after birth. She began suffering persistent bouts of diarrhea and vomiting, rashes that covered her body and infections, one after another.

It took two years to figure out what was wrong with her. She was diagnosed with adenosine deaminase deficiency, an extremely rare genetic disorder that cripples the immune system. Only a few dozen children in the world have it.

It involves a defect in the gene responsible for producing an enzyme critical to the functioning of the immune system--adenosine deaminase.

The enzyme is responsible for clearing the body of a toxin that is produced in the normal course of cell metabolism. If the body cannot rid itself of the toxin, deoxy-adenosine, it poisons the cells of the immune system. Without this enzyme, the body cannot fight infections. Ashi was developing high levels of the toxin, which was causing her immune system to fail.

Doctors at Rainbow Babies Hospital in Cleveland knew that NIH researchers--Blaese and Dr. W. French Anderson, now at USC, and Dr. Ken Culver--were exploring the possibility of using gene therapy to treat the disorder. But the idea had never before been tested.

Listening to Blaese and the others describe the potential and the risks, Ashi’s mother kept thinking: “I want this treatment for my daughter.”

She said that she was never frightened. Instead, “I was thrilled. I was grateful. I was happy for my little girl.”

At age 2, Ashi had begun taking a drug, PEG-ADA, that helped replace the missing enzyme and rid her body of some of the deadly toxin. Still, immune system tests on her showed that “things were not going so well,” Blaese said.

“The enzyme helped but I was very worried for Ashi that she would ultimately succumb to her disease, even though she was getting the drug,” Blaese says.

Others had failed to survive on the drug, which must be taken for life. And it is very expensive--as much as $400,000 a year, depending on the dose.

On Aug. 1, 1990, the three scientists received approval for their groundbreaking experiment from the Recombinant DNA Advisory Committee. In the drama of making its decision, committee members described the moment as “truly a historic occasion.”

On Sept. 4, 1990, the DeSilvas brought Ashi to NIH, where researchers took blood from her arm four separate times. She was very stoic, rarely crying during the repeated blood drawings. From her blood, cells were extracted that later would be put back into her body containing the new genes.

“There are a lot of things that go through your mind when you prepare to do something you’ve never done before,” Blaese remembered. “You agonize over whether you’ve done everything. . . . What scares you is if there’s something you haven’t thought about.”

Nothing went wrong. It was routine.

In fact, “she seemed like a happier kid the next day,” her mother recalled. “She was hugging us and kissing us. I remember telling the doctors, ‘I think you gave her the ‘happy’ gene.’ ”

Ashi stayed at NIH three days so she could be closely watched, then was sent home. Three weeks later she came back and the process was repeated.

Over the next two years, she received 10 more treatments--monthly at first, then gradually stretched out over more months. Her last session was in August 1992.

Nearly eight years after she received her final treatment, Ashi still has a high proportion of the new, corrected cells circulating in her body, doing what they are supposed to do.

“We looked at the level of enzyme produced by her T-cells, and before she had the treatment, it was zero,” Blaese said. “After each treatment, the number of cells producing the enzyme increased in number. In August 1992, more than 50% of her circulating cells carried the gene.

Ashi still receives a weekly injection of the drug, administered by her mother. But the dose, which is typically given by body weight, is the same as it was 10 years ago--meaning that she needs far less of it today than she otherwise would.

Some still question whether she is doing well because of the experiment or because of the drug or because of both. No one is willing to take the risk of stopping the drug.

Dr. Donald Kohn, director of gene therapy at Childrens Hospital Los Angeles, in 1993 tried a procedure similar to the one that Ashi soon will receive on three newborns with the same immune disorder as Ashanthi. His team transplanted gene-corrected stem cells obtained from the babies’ umbilical cord blood when they were only 4 days old.

That experiment proved safe but disappointing. Only a few new corrected blood cells were produced. The three babies he worked with--approaching age 7--are still taking the drug PEG-ADA.

But he agrees with Blaese that improved techniques could make a big difference this time, adding that all of these attempts represent “very important, positive steps.”

There are better methods for growing cells, and a more active retrovirus to use to introduce the new cells into the body, raising the odds that it will work.

And, if so, Ashi’s body will stop making cells with the defective gene and only make cells with the right gene--in other words, a cure for her--and a boon for gene therapy.