Death clouds a gene-therapy's future

The death of a patient in a clinical trial run by Seattle-based Targeted Genetics is raising questions about a promising gene-therapy method until now thought to be safe.

The "adeno-associated virus" (AAV) used to deliver the company's drug for severe inflammatory arthritis has not previously caused any serious problems, so "no one knows why it happened," said Dr. David Russell, a professor of medicine at the University of Washington who specializes in gene therapy.

"We're all just waiting to see if it had anything to do with AAV," he said.

The tragedy is also a financial blow for Targeted, whose shares plummeted for a second day Friday and lost nearly 40 percent this past week.

The company reported Tuesday that a patient enrolled in experiments for its leading drug candidate had become seriously ill, and said the trial was being suspended as a precautionary measure. Two days later, the company and the U.S. Food and Drug Administration said the unidentified patient was dead.

Nothing else has been said of the patient's last moments, whereabouts or even cause of death. Both the company and the authorities say that the cause of death hasn't been established yet, and it's unclear whether the serious adverse effects reported earlier are related to the therapy at all.

But because the illness closely followed the patient's second injection with the drug, the agency is taking a closer look at all trials using the same type of gene therapy.

No other cases of serious adverse effects — which include life-threatening conditions, disabilities or admission into a hospital — have been reported in any of the 29 AAV-related clinical trials currently supervised by the FDA, the agency says. About 600 patients have been treated with those therapies.

The death is the second in the history of gene-therapy trials, experts said. In 1999, 18-year old Jesse Gelsinger, part of a University of Pennsylvania study on an inherited liver disease, died of a massive immune reaction to a gene-therapy treatment.

There's a business link to Targeted Genetics from that case: The UPenn experiment was led by Dr. James Wilson, whose company, Genovo, licensed the technology used in the trial. Targeted Genetics acquired Genovo in 2000 for $66 million in stock.

The company, however, says that there's no Genovo technology in its inflammatory-arthritis drug.

And the drug tested in the UPenn trial was based on a different type of virus, said Russell.

Targeted Genetics shares fell again Friday, following news of the patient's death. Shares traded at $1.65, down 42 cents or 20.3 percent.

Researchers like to use adeno-associated viruses because they typically produce a very mild reaction in the body's immune system, making them less problematic to administer. When the viruses infect a cell, they burrow into a specific part of its genome, making it easy for scientists to use them as vessels to replace faulty genes. Adeno-associated viruses are "very efficient at delivering genes to a lot of different organs in the body," says Russell.

If the virus vehicle that carries Targeted Genetics' therapy turns out to have played a role in the patient's death, "it would be an important finding" for the entire field, said Russell. "It would indicate that we need to take that into account when we design our trials."Ample data in clinical and preclinical trials have indicated that adeno-associated viruses are safe to administer, but some toxicity has been demonstrated in animals, Russell said.

In an article published Friday in the academic journal Science, Russell and other University of Washington researchers described how mice injected with a type of adeno-associated virus developed cancer. However, the event is presumably a phenomenon unrelated to the Targeted Genetics case and it has only been shown to occur in mice, Russell said.

The Targeted Genetics trial was the only one that involved administering more than one dose of the drug, FDA spokeswoman Karen Riley said.

Some 127 patients have received an initial dose of the active drug or placebo, including 74 that received a second dose of the drug, Targeted Genetics said. All patients are currently being monitored, the company said.

The study was being conducted in 22 centers across the country, including Seattle.

Ángel González: 206-515-5644 or agonzalez@seattletimes.com