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Gene therapy trials are restored by FDA despite cancer cases

By Raja Mishra, Globe Staff, 3/1/2003

SILVER SPRING, Md. -- Restoring momentum to a beleaguered experimental medical field, federal officials yesterday permitted 27 recently halted gene therapy patient trials to proceed despite revelations that the advanced technique caused cancer in two young patients.

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Federal officials froze the trials last December after French researchers reported the cancer cases, raising fears among some researchers that gene therapy would remain under an ethical cloud for years. The much-touted field, in which doctors attempt to cure patients by inserting genes into them, is still recovering from the 1999 death of a test patient.

The suspended trials were a small but marquee group among the more than 200 US gene therapy patient experiments underway, cleverly using a common virus to deliver genes inside cells that could potentially treat cancer, HIV, multiple sclerosis, immune disorders, and other ailments. The use of the virus had actually worked well in treating so-called ''bubble boy syndrome,'' but the cancer cases made clear that the virus can do damage as well.

But yesterday, a research panel convened by the Food and Drug Administration agreed the technique's healing potential outweighed the cancer risk. They voted, with only one ''nay'' among 21 members, to green-light the suspended trials. The endorsement, however, came with a caveat: Each gene therapy researcher involved in those trials must convince federal officials that all patients undergoing the experimental treatments are amply warned of its cancer risks.

The FDA will ''now go back and look at each trial in an active mode,'' said Dr. Philip D. Noguchi, the FDA's chief gene therapy regulator. ''We'll work with each researcher through all the issues.''

Patient safety advocate Paul Gelsinger, whose teenage son Jesse's death in a 1999 gene therapy experiment prompted a federal overhaul of the research, approved of the panel's decision, particularly praising its openness, a contrast with the initial secrecy surrounding his son's death.

The panel refused to give the go-ahead to two recently suspended US trials similar to the French research that gave the two boys cancer. They involve X-linked severe combined immune deficiency disease or X-SCID, commonly known as ''bubble boy'' disease after a 1980s high-profile case in which a patient lived within a sealed plastic enclosure to guard against infection. The FDA will review each patient involved in these two trials to determine whether they possess a heightened risk of developing cancer, and if all means of conventional treatment have been exhausted. A third related trial, involving a variation of SCID, will also be restricted in the same way.

The two French cancer cases arose in X-SCID patients, who were born without a critical immune system gene, making them extremely vulnerable to viruses. Even the common cold can be a mortal threat, and many must live in sealed sterile rooms. Most die during childhood. A matched bone marrow transplant can help, though these risky and rare procedures often fail.

Gene therapy scored its first -- and only -- success to date against this daunting condition.

Researchers at the Necker Hospital in Paris removed the faulty immune cells from patients, all infants. The cells were mixed in a lab dish with a retrovirus, a type of virus that wedges its own DNA directly into a patient's DNA. But this was no ordinary retrovirus: researchers stripped it of dangerous genes, then inserted the very immune system gene the patients lacked. In the lab dish, the retrovirus did its job, infecting the bone marrow cells. The modified bone marrow cells were then put back in patients.

It worked, generating headlines around the world. The bone marrow spread the corrective gene, quickly rebuilding the infants' immune systems. Nine of 11 patients responded, and were soon discharged from the hospital to live, for the first time in their lives, like normal children.

The success, in 2001, electrified the field, which was still reeling from Jesse Gelsinger's death.

But troubling news arrived last September. One boy developed leukemia, a blood cancer. Analysis indicated the retrovirus had wedged itself on top of a gene called LMO2, involved in cell replication. The disturbed LMO2 gene caused the bone marrow cells to multiply uncontrollably -- and a patient that once desperately needed healthy immune cells had too many, causing cancer.

The boy was put on high-dose chemotherapy. But researchers figured the cancer was a fluke. But in December came a second leukemia case, prompting the FDA to suspend all gene therapy trials that use a retrovirus to deliver treatment.

The two children with leukemia are ''doing well,'' said Dr. Marina Cavazzana-Calvo of Necker University. The other seven patients responding to the treatment continue to live normal lives.

The FDA panel, comprised of researchers, ethicists, and patient advocates, unanimously agreed that bubble boy patients should only get gene therapy if all other treatment options were exhausted. Before, some researchers viewed gene therapy as equivalent to the conventional treatment, bone marrow transplantation, rather than last ditch.

''It's not easy striking the right balance here,'' said panel member and ethicist Thomas Murray of the Hastings Center in New York. Murray supported lifting the suspension of the 27 gene therapy trials. The lone dissenter on that vote was John Coffin of Tufts University, who said that researchers still know little about the biology behind the cancerous side effects, and approvingly cited the cautious approach of another high-profile scientific probe.

''We're not going to send space shuttles up until we find out what happened to the Columbia,'' he said.

Raja Mishra can be reached at

This story ran on page A3 of the Boston Globe on 3/1/2003.
© Copyright 2003 Globe Newspaper Company.

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