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GENES & HUMANS: Fungus infected woman who died after gene therapy




                                  PART 1


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TITLE:  FUNGUS INFECTED WOMAN WHO DIED AFTER GENE THERAPY

SOURCE: The Washington Post, USA

AUTHOR: Rick Weiss

URL:    http://www.washingtonpost.com/wp-dyn/content/article/2007/08/16/AR2007081602322.html

DATE:   17.08.2007

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FUNGUS INFECTED WOMAN WHO DIED AFTER GENE THERAPY

The 36-year-old Illinois woman who died last month after being treated with an experimental gene therapy was infected with a fungus that usually causes only a mild illness. But the infection spun out of control and ravaged her organs, suggesting that her immune system was seriously impaired, said a doctor who is part of the medical investigation.

The woman’s body was also teeming with a cold-sore virus that the body normally keeps in check, another indication of a faltering immune system. And because of a tear inside her abdomen -- perhaps caused by infection, perhaps by injury -- she had an internal blood clot the size of a watermelon.

No formal cause of death has been declared for Jolee Mohr, who died July 24. Mohr had been generally healthy until July 2, when trillions of genetically engineered viruses were injected into her right knee in an experimental treatment for her rheumatoid arthritis.

The injected viruses were genetically modified so they would suppress the immune system -- which is responsible for the inflammation of rheumatoid arthritis -- only in her knee. Doctors hope that tests on tissue specimens and blood samples will tell whether the treatment’s effects somehow spread from the joint to other parts of Mohr’s body.

The picture will be complicated, however, because Mohr was also taking conventional immune-suppressing drugs for her arthritis. One of those in particular, adalimumab, whose brand name is Humira, is known to make patients susceptible to histoplasmosis, the kind of fungal infection that Mohr had. Inexplicably, Mohr suddenly became ill in July even though she had been taking that drug for years and the fungus that causes histoplasmosis is ubiquitous in the area where she lived.

”It’s a major mystery,” said Kyle Hogarth, who heads the intensive care unit at the University of Chicago Medical Center, where Mohr was transferred days before she died.

The company behind the medical experiment, Targeted Genetics of Seattle, has said that the treatment has an excellent safety record and that none of the more than 100 other volunteers who got the injections suffered anything more than short-lived side effects.

Hogarth and about 20 other doctors and scientists are investigating the death with help from experts in an immune system factor called tumor necrosis factor-alpha, or TNF-alpha, which is suppressed by the experimental genetic treatment and by Humira.

The autopsy was done with particular care, using sterile techniques more commonly associated with surgery on the living because of the importance of getting good clinical evidence, Hogarth said.

”Think ’CSI,’ without the criminal implications,” he said, adding that he suspects it will take one to two months to complete the tests.

The fungus found throughout Mohr’s body is Histoplasma capsulatum. It is common in airborne dust and bird droppings in the Mississippi and Ohio river valleys and generally causes a mild respiratory illness when inhaled. But in people whose immune systems are compromised -- because of AIDS or cancer chemotherapy, for example -- the fungal cells can spread to other organs and blossom quickly into fatal infections.

”It was in her liver. In the blood. It was essentially everywhere,” Hogarth said.

It is not known whether Mohr’s infection was recently acquired or was old and recently reactivated. In healthy people, the immune system walls off the fungal cells in structures called granulomas, whose integrity is maintained by TNF-alpha. When TNF-alpha is suppressed, the granulomas can dissolve and release the still-living fungi.

Experts in gene therapy are eagerly awaiting the test results. A link to the death would be a painful setback for the research field, which attempts to treat diseases by giving people new genes.

”Gene therapy holds a great deal of potential,” said Arthur Nienhuis of St. Jude Children’s Research Hospital in Memphis, who is president of the American Society of Gene Therapy. He noted that after more than a decade of failures and a handful of instances in which gene-based treatments caused leukemia in volunteers, the approach has recently produced what appear to be its first cures. More than a dozen children born with genetically defective immune systems are now living normal lives because of injections of new genes.

A Targeted Genetics spokeswoman declined to comment on the autopsy findings, saying the company will make a full presentation at a National Institutes of Health meeting on Sept. 17.



                                  PART 2

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TITLE:  MAN SEEKS ANSWERS IN WIFE‘S DEATH AFTER EXPERIMENTAL GENE THERAPY

SOURCE: Seattle Post - Intelligencer, USA

AUTHOR: The Associated Press, by Carla K. Johnson

URL:    http://seattlepi.nwsource.com/local/6420AP_IL_Gene_Therapy.html

DATE:   11.08.2007

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MAN SEEKS ANSWERS IN WIFE‘S DEATH AFTER EXPERIMENTAL GENE THERAPY

CHICAGO -- An Illinois man wants to know exactly why his 36-year-old wife died of internal bleeding and organ failure after taking part in medical research on an experimental drug she hoped would help her arthritis.

The July 24 death of Jolee Mohr of Taylorville prompted the government to suspend a Seattle company’s gene therapy study - and begin a review of the safety of 28 others around the country. Mohr, the mother of a 5-year-old daughter, received the experimental injections at a central Illinois clinic.

”Rheumatoid arthritis affected her whole body, but especially her right side,” Robb Mohr told the (Bloomington) Pantagraph. His wife’s death came 22 days after receiving her second injection of an experimental drug made of genetically engineered viruses.

Targeted Genetics Corp. of Seattle has halted the study, and more than 100 patients involved are being evaluated, said company spokeswoman Stacie Byars. The company believes it’s too early to speculate on the woman’s cause of death, Byars said.

Mohr said he believes his wife thought the drug would help her, even though the research was to determine the drug’s safety, rather than its effectiveness. The University of Chicago Medical Center, where Jolee Mohr died, is conducting an investigation in an attempt to determine the cause of death.

”By the time she got to us, she was in liver failure and kidney failure, she was on a ventilator and she was septic” or responding to severe infection, hospital spokesman John Easton told The Associated Press. The hospital will send tissue samples to multiple labs for testing.

Alan Milstein, a New Jersey attorney who is representing Robb Mohr in a possible civil lawsuit, said Jolee Mohr believed the experimental therapy would be in her best interests.

”She wasn’t going to risk her life for science or medicine or the profits of some company,” Milstein told The Associated Press on Saturday. ”She had mild rheumatoid arthritis.”

Milstein also represented 18-year-old Jesse Gelsinger, who died in 1999 in his fourth day of a gene therapy experiment at the University of Pennsylvania. Gelsinger had suffered from an inherited disorder that blocks the body from properly processing nitrogen. The Food and Drug Administration concluded that the gene therapy injection intended to try to cure him instead killed him.

Milstein said he’s not sure who’s to blame for Jolee Mohr’s death, but ”we certainly believe the death was connected to the research trial she was in.”

Twenty-eight other gene therapy studies have been reported to the FDA that used, or are using, the same virus, called adeno-associated virus or AAV.

The therapy uses AAV to deliver a gene that in turn blocks tumor necrosis factor, a substance that fuels the joint inflammation behind crippling forms of arthritis. Drugs that block TNF already are widely used to treat rheumatoid arthritis and other conditions, but a gene therapy approach is new.

The FDA has said that it was not aware of any serious side effects in any of the AAV studies but that as a precaution, officials are reviewing the ones still actively treating patients.

In addition, the National Institutes of Health’s advisory committee on gene therapy will meet in September to discuss the potential scientific implications of Mohr’s death.


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