Suspended Gene Therapy Test Had Drawn Early Questions

By Rick Weiss
Washington Post Staff Writer
Saturday, July 28, 2007

A gene therapy experiment that has triggered a federal investigation after the death of a patient on Tuesday raised a variety of concerns when it was first proposed to federal reviewers in 2003.

Unlike the vast majority of such proposals, all of which aim to treat diseases by giving patients new genes, the plan to inject trillions of genetically engineered viruses into the joints of patients with arthritis was flagged for a special public review by the federal Recombinant DNA Advisory Committee, part of the National Institutes of Health.

At that Sept. 17, 2003, meeting, representatives of the sponsoring company, Targeted Genetics Corp. of Seattle, listened as a panel of experts wondered aloud why such a novel and possibly risky approach was to be offered to patients who were not especially ill, including some who had not even tried standard treatments.

Reviewers questioned the justification for the study, given that animal studies had found only a "limited correlation" between the treatment and any improvements in subjects' condition. And they asked for more assurance that the engineered viruses were not going to spread around the body or cause untoward immune system reactions in patients.

Some also expressed concern that the informed consent document the researchers planned to use to describe the risks and benefits to participating patients was not upfront enough about the fact that the study was unlikely to help them and was designed merely to test the new approach's safety.

"Emphasizing this information might encourage potential subjects to think more critically about their participation," one reviewer said, according to the meeting minutes.

The proposed 32-patient phase-1 study eventually went forward with no serious side effects, said Barrie Carter, the company's chief scientific officer.

That led to federal approval of an expanded phase of the study, this time at 20 locations around the country. About 100 patients had received the treatment -- none with any serious side effects, Carter said -- when one became inexplicably ill late last week.

The study was suspended immediately. The patient died four days later.

Company officials yesterday said they are still looking into the cause of death. So is the Food and Drug Administration. No details have been released, including how many doses the patient received. The death may be unrelated to the treatment, but the close timing warrants a full investigation, company and government officials said.

Carter and Pervin Anklesaria, Targeted Genetics's head of therapeutic development, said yesterday that the company had gone ahead with the studies only after addressing the NIH reviewers' concerns.

The company officials said there was a rationale for including only mildly affected and previously untreated patients at first: Any side effects could be attributed to the new therapy and not to whatever medicine they might have been taking.

They acknowledged that some animals had shown improvement in joints on the opposite side of the body from those injected -- an observation that had raised reviewers' concerns that the viruses might be spreading throughout the body, with possible ill effects in the long run. But Carter said that phenomenon has been seen with many kinds of arthritis treatments and remains unexplained.

Most important, both said, tests on animals -- and more recently on some patients -- have all failed to find evidence that the viruses, which produce a protein that can block the arthritis-related inflammation, escape from the joint where they are injected.

Mark A. Kay, a Stanford University professor who has led gene therapy trials that, like the arthritis study, used "adeno-associated viruses," said he was surprised by the death, given the virus's safety record.

In the one instance of trouble in his studies, he said, a patient's immune system attacked his own liver cells after those cells became infected with the virus, causing a "mild and self-limited" decline in liver function.

"I don't think people should panic," Kay said. "It's devastating, and my heart goes out to the family. But people have to sit back and see what happened before jumping to conclusions."

Theodore Friedmann, director of the gene therapy program at the University of California at San Diego School of Medicine, chaired the committee that reviewed the initial 2003 arthritis proposal. He said he does not recall the meeting, but he said the field, despite its occasional setbacks, needs to get over its long-standing "hangdog attitude."

"It's a difficult technology. It's early. It's immature still. But it is attacking some very nasty diseases," Friedmann said, "and in some cases, it is having a benefit."

On a day when all stocks dropped sharply, shares of Targeted Genetics fell 42 cents yesterday to $1.65 in Nasdaq Stock Market composite trading, the lowest price since the stock was first sold to the public in May 1994.

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