No decision yet on whether gene therapy caused death

BETHESDA, Md. — A top-level scientific panel discussed in painstaking detail Monday the last moments of Jolee Mohr, who died after her knee was injected with an experimental gene therapy developed by Seattle's Targeted Genetics. But the group failed to answer the key issue posed by her husband.

"The biggest question I have is, would my wife still be alive today if she had not participated in the study?" said Robb Mohr, visibly shaken as he addressed the panel toward the end of the four-hour session.

"We don't know," responded Howard Federoff, chairman of the Recombinant DNA Advisory Committee (RAC) at the National Institutes of Health. He added that the panel would "reserve judgment" until all data is gathered, possibly by the group's next meeting in December.

Despite nearly eight weeks of study since the Illinois woman died July 24, scientists still don't agree on the immediate cause of death. The role of Targeted Genetics' drug, a treatment for rheumatoid arthritis, is also still in dispute.

They do agree Jolee Mohr's immune system was wrecked, leading to a massive fungal infection and death. But some experts pondered whether death came from the infection attacking her liver or from a large, tumorlike mass of blood that displaced her organs and crushed her lungs. The source of the mass, called a hematoma, is unknown.

"She may have died with liver disease, but not necessarily of liver disease," said Leonard Seeff, a senior scientist at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda.

Mohr's tissue samples are still being analyzed at the University of Chicago, where scientists seek to determine whether the Targeted Genetics drug had spread beyond the 36-year-old woman's knee.

The drug aims to weaken the immune system in the joints to reduce the inflammation that leads to arthritis. But it was designed to stay where it's injected, without spreading.

The Targeted Genetics drug consists of a gene riding on an adeno-associated virus (AAV), a carrier many scientists find promising because of its apparent mildness.

If AAV is found guilty of uncontrolled propagation beyond the knee or heavy toxicity, it would deal a heavy blow to Targeted Genetics — whose pipeline of drug candidates relies on AAVs — and to the whole field of gene therapy.

The clinical trial has been suspended pending firm conclusions from the Chicago investigation.

Mohr's death underscores the question of whether gene therapy, a biotechnology frontier with no therapy yet approved, should be tried in patients with non-lethal diseases.

Robb Mohr's lawyer, Alan Milstein, maintains that Jolee Mohr and others were unduly exposed to a very risky therapy.

But some panelists said that even though rheumatoid arthritis is not fatal, the chance to beat it was worth the risk associated with clinical trials.

The disease, which tends to focus on the joints, causes "pain and swelling and deformities," said Mary Crow, rheumatology research chief at New York's Hospital for Special Surgery. "It can cause significant disability."

Jolee Mohr had participated in another rheumatoid-arthritis experimental trial, for the Immunex drug Enbrel, and had gone through other therapies for the condition, Hogarth said.

In other patients, several of those therapies have been linked to weakened immune systems that opened the door to fungal infections.

The fact that Mohr participated in two trials suggests "she really wanted to try medical science," said Mark Kay, a gene-therapy expert at Stanford University who listened to the meeting's webcast. "Even though people agree to do these trials with the idea that it's an early safety study, a lot of them in the back of their mind hope the trials can help them."

At least 500 patients have been exposed to AAV-related therapies, and there have been 34 adverse-event reports possibly related to the therapy, said Jacqueline Corrigan-Curay, acting executive secretary of the RAC panel. Mohr's death is the only one associated with AAV.

While the Chicago team has to grapple with limited tissue samples and doesn't expect to conclude tests in less than three to four weeks, it detected traces of the drug in spleen and liver tissue. The proportion is similar to results obtained — and deemed safe — in Targeted Genetics' clinical and preclinical data.

The company says the findings underscore its claim that the drug was "unlikely" to have contributed to Mohr's death. The data "was very positive," said spokeswoman Stacie Byars.

Mohr's lawyer, Milstein, has a different view. "I think it's significant that they found that data on the liver and the spleen," he said.

Stanford's Kay said that so far, the evidence points to the innocence of gene therapy.

"I think that it's looking more and more like it's unrelated," Kay said. "Can you absolutely conclude there wasn't some contribution? Not yet. But there was nothing that was presented today that makes me think that in any way [the death] was related to gene therapy."

Robb Mohr, who walked out of the room when University of Chicago scientists went into clinical details of his wife's death, is anxious to see the end of the investigation. "I feel confident that the University of Chicago will get to the bottom of this," he said.

The company plans a conference call today to discuss the panel's review. Targeted Genetics shares closed Monday at $1.86, down 10 cents.

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