Gene Therapy Study Suspended

[antiquity]

Gene Therapy Study Suspended
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By LAURAN NEERGAARD : AP Medical Writer
Oct 3, 2002 : 2:58 pm ET

WASHINGTON (AP) -- Scientists have suspended studies of the first gene therapy ever to work -- a treatment that appears to cure a rare immune disorder called "bubble boy disease" -- as they scramble to tell whether the therapy gave a French toddler a leukemia-like side effect.

It's unclear if the gene therapy actually caused the boy's illness, although there are clues that a virus used in the treatment may be to blame. No other children given gene therapy for the disease -- severe combined immunodeficiency, or SCID -- have shown such a side effect.

The French boy's gene therapy, performed in October 1999, was successful, giving him a strong immune system. But in late summer, doctors discovered his body had far overproduced a type of white blood cell, a disorder they call leukemia-like. Now 3, he is responding well to chemotherapy, scientists said Thursday.

France and the United States suspended further studies of gene therapy for SCID while they evaluate what happened and notify parents of previous gene therapy recipients of the possible risk.

Advisers to the Food and Drug Administration will consult with French scientists and meet next Thursday to debate what steps are needed before the U.S. studies could resume, said Dr. Phil Noguchi, FDA's director of gene therapy.

The highly publicized moves were unusual -- in studies of regular drugs, many people typically become ill before research is put on hold or generates public debate. But gene therapy has been a publicly charged topic since the 1999 death of 18-year-old Jesse Gelsinger, who was given a different type of gene therapy for another disease. Many scientists now believe that openly discussing potential risks as they're discovered is important to educate people about the new technology.

SCID gene therapy "has been a spectacularly successful endeavor up to this point," said Savio Woo of the American Society of Gene Therapy. If it truly poses a risk of leukemia, "then we have discovered a new enemy. Once we know the enemy, then the experts in the field will...be able to come up with strategies of how to deal with it."

SCID is a very rare inherited disease, occurring in about 1 in 75,000 births, in which patients' bodies don't make certain proteins crucial to developing disease-fighting immune cells. Without treatment they die very young. The best-known victim was David, Houston's famous "bubble boy" who lived in a germ-proof enclosure until his death at age 12 in 1984.

The most severe form, X-SCID, afflicts only boys.

Those given a bone marrow transplant from a genetically compatible brother or sister are likely to be cured -- but only 20 percent of X-SCID patients have a sibling who's a good match.

When boys without a good match undergo a transplant anyway, a quarter die, said Dr. Donald Kohn of Children's Hospital in Los Angeles.

Hence the excitement when gene therapy worked in nine of the 10 X-SCID patients treated so far at Paris' Hopital Necker-Enfants Malades.

Dr. Alain Fischer drew bone marrow from the boys and culled immune cell-creating stem cells from it. He mixed in a virus containing a gene that makes the immune-system protein the boys' bodies lacked. Injected back into the boys, the stem cells worked properly.

Scientists long theorized -- and warned study participants -- that cancer might occur if the therapy's virus lodged near certain genes that control cell growth and affected them, too, Kohn said.

But with a total of 13 X-SCID gene therapy recipients in France and Britain, and 19 U.S. and Italian children given gene therapy for a related illness called SCID-ADA, the French case marks the first such side effect.

All SCID studies use a similar virus. As a result, the FDA has temporarily suspended two X-SCID studies poised to begin at Kohn's hospital and the National Institutes of Health, plus Kohn's own study that recently gave gene therapy to four SCID-ADA patients.

http://www.herald-sun.com/healthmed/34-273195.html

Copyright 2002 Associated Press. All rights reserved.

[Max]

Gene Therapy Defended Despite New Setback
Fri Oct 4,11:51 PM ET
By Adam Marcus
HealthScoutNews Reporter

FRIDAY, Oct. 4 (HealthScoutNews) -- Gene therapy researchers today defended their field despite news that a mysterious leukemia-like side effect has forced the halt of four trials of the treatment in children with deadly immune system defects.



Health officials in the United States and Europe took that step last month after a 3-year-old boy in France undergoing gene therapy to cure a condition called X-linked severe combined immunodeficiency disease, or X-SCID, experienced runaway growth of his immune system's T cells. The boy is receiving chemotherapy and appears to be doing well, people familiar with the case said.

Nine other children in the French study also cured of their disease have not shown signs of the same side effect, according to the American Society of Gene Therapy. The study is being led by Dr. Alain Fischer of the Necker Hospital in Paris.

Researchers are not certain gene therapy is to blame for the reaction, though it seems likely. Children with X-SCID -- sometimes called "bubble babies" -- have virtually no T cells. So in the absence of treatment, the boy would not have developed runaway production of them. Moreover, scientists have known that the corrective gene, which enters the body hitched to a retrovirus, could in theory lodge in or next to a cancer-promoting gene and cause trouble.

"We knew the risk that this therapy carried with it, and we've always presented that to all our patients," said Dr. Fabio Candotti, a gene therapy expert at the National Institutes of Health ( news - web sites) and leader of one of the suspended studies.

Dr. Mark Kay, a Stanford University gene therapy expert, said it's plausible the French boy's condition wasn't a result of his treatment. "The thing that's probably most important is to see where [the corrective gene] inserted." Kay is running a study of gene therapy in adults who have the blood-clotting disorder hemophilia. That trial is not affected by the stoppage.

Candotti called the latest problem a temporary setback for gene therapy and said it wouldn't undermine its long-term viability. Nearly three dozen children have undergone the procedure for SCID, and roughly 1,000 people have had gene therapy using retroviruses. Until now, none had developed the leukemia-like condition.

The first gene therapy trial a decade ago attempted to correct a form of SCID in which the patient did not make enough of a key immune enzyme. The method has been applied to a wide range of other ailments, from head and neck cancers to heart problems. But to date, it has led to cures only in children with SCID.

Because gene therapy for SCID babies involves a one-time treatment, pausing the studies simply means that no new patients will be enrolled in the trials. Those who've already received the therapy will be monitored for signs of trouble.

The studies involved children who failed bone marrow transplants and therefore had no other chance of surviving their disease. Although children who receive marrow from a sibling with a perfect cell match have an excellent chance of success, only about 20 percent to 25 percent of patients are so well-paired, Candotti said. For the rest, even those with a partial match, the death rate is 20 percent or worse.

"One would say that [gene therapy] is more successful and less toxic" than bone marrow transplants for 75 percent to 80 percent of patients, Candotti said.

The U.S. Food and Drug Administration ( news - web sites) will take up the fate of the stalled gene therapy trials at a meeting next week. Two of the three U.S. studies have not enrolled any patients yet and involve a different form of SCID from the French research.

Dr. W. French Anderson, who helped lead the first gene therapy trial in the United States, said he supported the decision to put a hold on the studies "until we can figure out what happened in France."

Anderson, of the University of Southern California's Keck School of Medicine in Los Angeles, said regulators were concerned about precisely such a complication when he and his colleagues were preparing to conduct their study a decade ago.

However, they could find only three cases of the leukemia-like condition in hundreds of lab animals, and those three episodes occurred in monkeys exposed to extreme conditions of immune suppression. "Because [the risk] was low, that's the reason the FDA and the NIH let us go ahead," Anderson said. Even so, he added, "We knew it was going to happen, and sadly it has happened."

Anderson remains confident in the future of gene therapy. Yet he said the latest incident is a warning to scientists who might try to apply it to conditions that aren't life-threatening, like baldness. "I've been arguing this for 30 years: Gene therapy is a very powerful technology, and it should not be used for any other purpose but for the treatment of serious disease," Anderson said.

Dr. Jonathan Goldsmith, vice president of medical affairs for the Immune Deficiency Foundation in Towson, Md., backed the decision to halt the gene therapy trials until scientists determine what caused the French boy's illness. "It could be gene therapy itself, it could be something to do with the patient, or it could be a combination," he said.

But Goldsmith said the investigation must be quick. Roughly one in 75,000 American babies is diagnosed with SCID each year. If the suspension lasts six months, 25 to 50 infants might be born with disease in that time. Both gene therapy and bone marrow transplants "should be done as soon as possible," Goldsmith added.

The Institute of Medicine ( news - web sites) released a report yesterday calling on Congress to require researchers in both public and private institutions to better safeguard people enrolled in clinical trials. The study was commissioned after the death in 1999 of Jesse Gelsinger, 18, who had been participating in a gene therapy study at the University of Pennsylvania.

What To Do

To learn more about gene therapy research, visit MEDLINEplus. For more on SCID, try the Immune Deficiency Foundation.

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"It was once written "To thine own self be true". But how do we know who we really are? Every man must confront the monster within himself, if he is ever to find peace without. .." Outer Limits(Monster)

[Max]

Gene Therapy Trials May Restart
Fri Oct 11, 4:06 AM ET
By LAURAN NEERGAARD, AP Medical Writer

Gene therapy that seems to cure an often fatal immune disorder also likely gave a French toddler a leukemia-like illness, but U.S. scientists want the genetic experiments restarted anyway - calling the risk too low to deprive desperate children of treatment.



The Food and Drug Administration (news - web sites) called an emergency meeting of its scientific advisers Thursday to decide whether three U.S. gene therapy experiments recently suspended because of the French boy's illness should resume. France also suspended the experiment.

The disorder often known as "bubble boy disease" - formally called severe combined immunodeficiency, or SCID - is the only disease where gene therapy has ever worked.

The toddler is the first recipient of gene therapy for any disease to suffer a cancerous side effect. But scientists have long warned that cancer is a possible risk if the virus used to deliver new genes into a patient's body slips into the wrong place.

The evidence "is pretty convincing" that now that has happened, said Dr. Philip Noguchi of the Food and Drug Administration, after French researchers showed evidence the virus they used affected a cancer-promoting gene in the boy's body more than a year after it cured his SCID.

It took another year and a half before the boy developed leukemia-like symptoms. Chemotherapy appears to be working, and tests soon should tell if the 3-year-old is in remission, Paris' Dr. Alain Fischer told the FDA meeting.

Still, there is only one report of gene therapy-linked leukemia - while some popular chemotherapies carry a 10 percent risk that in curing today's cancer the patient will get leukemia years later, cautioned Dr. Crystal Mackall of the National Cancer Institute (news - web sites).

"You can be doing harm when you withhold a promising treatment," added Dr. Joanne Kurtzberg of Duke University, echoing a woman who told the panel that the experiment is her 10-year-old grandson's last hope.

The FDA advisers ultimately recommended that gene therapy experiments be reopened to SCID patients who don't have the option of a bone marrow transplant from a well-matched donor, today's best treatment. The FDA usually follows its advisers' recommendations.

But some panelists worried that the leukemia finding's implications go beyond SCID to every gene therapy experiment that ever used a retrovirus, a kind of virus that permanently invades cells.

"We owe an extra measure of regard to all the people still alive who volunteered for gene therapy. They should be told about this risk and check for it," said Abby Meyers of the National Organization for Rare Disorders.

She angrily noted that eight years after Congress ordered the FDA to create a registry of gene recipients in case long-term side affects ever appear, the agency hasn't done so. The FDA still is working to ensure survivors of all 150 retroviral gene therapy studies ever done are notified of the French case, Noguchi said.

People signing up for future retroviral gene therapy for any disease must be more strongly warned that leukemia is a risk - with specific discussion of the French case, the advisers added.

Babies with SCID are born without the ability to produce disease-fighting immune cells. The best known victim was David, Houston's famous "bubble boy" who lived in a germ-proof enclosure until his death at age 12 in 1984.

There are some SCID treatments, including bone marrow transplants that can allow patients to live normal lives. But transplant success varies widely, and many children still die young.

So Fischer generated great excitement when his gene therapy apparently cured nine of the 11 children he treated, all with the most severe type of SCID-type, called X-SCID, that afflicts only boys.

Similar U.S. studies poised to begin have been put on hold.

Fischer took bone marrow from the boys and culled from it skin cells that are supposed to create blood cells. He mixed in a retrovirus containing the immune-creating gene their bodies lacked, and reinjected the stem cells, which in nine boys started working properly.

Intricate molecular studies of the toddler who got the leukemia-like illness three years after his gene therapy found the virus that delivered the SCID-curing gene also inserted itself into numerous other spots on cells, including a leukemia-promoting gene.

That alone likely wasn't enough to sicken him, several scientists said, but may have been the final piece of bad luck on top of a family predisposition to cancer and other still unknown factors.

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"Events in our past seem to slip further away with time. But what happens when they circle back and meet us head on....in the present? Before we allow ourselves to be consumed by our regrets, we should remember the mistakes we make in life are not so important as the lessons we draw from them.." Outer Limits(Last supper)