July 27, 2007 -- The death of a patient enrolled in the clinical trial of an experimental gene therapy is the third black mark for the treatment approach since 1999 -- and one that doctors fear has the potential to stall future research.
The death has spurred the U.S. Food and Drug Administration (FDA) to halt the trial and begin safety reviews of 28 other gene therapy trials around the country.
According to an FDA press release issued Thursday, the Seattle-based Targeted Genetics Corp., which conducted the trial, informed the FDA of the death July 24.
The trial was designed to test the effectiveness of a treatment for active inflammatory arthritis called tgAAC94.
It is not yet clear whether the drug being used directly led to the patient's death, or whether other causes are to blame. Still, in response to the death, the FDA has launched an investigation of the trial, which began in October 2005 and involved 127 subjects who may have received the drug.
According to the FDA statement, none of the other subjects are reported to have experienced similar complications, and the patient's illness was related in time to the receipt of a second injection of the product.
But gene therapy researchers say they are already worried that the death could represent a major setback for the technology, regardless of the results of the investigation.
"Gene therapy may be an important future effort, and it is disconcerting that something like this has happened," said Dr. Lee Simon, associate clinical professor of medicine at Harvard Medical School, who called the announcement "interesting and troubling."
Other doctors agreed.
"It is certainly a troubling development," said Dr. David Fox, chief of rheumatology at the University of Michigan Medical School. "It will be important to determine what caused this patient's death and whether it was due to the gene therapy treatment."
Dr. Michael Becker, a rheumatologist at the University of Chicago Medical Center, said that his first reaction to news of the trial was "sadness at the death of the patient and concern about its implications relevant to gene therapy."
Gene Therapy Promise -- and Pitfalls
A number of diseases and conditions are caused by defective genes in the patient's cells. The idea behind gene therapy is to replace these defective, disease-causing genes in a patient's body with normal genes, thus alleviating the source of many genetic diseases.
In order to do this, scientists need a way to get the replacement genes into the patient's cells. The tool of choice is usually a virus that has been modified to carry the new gene. In the same way that a normal virus would infect a cell with its own genetic material, the designer virus -- known as a vector -- infiltrates the cell and delivers the replacement gene.
In recent years, the possibilities of such treatments have heartened disease researchers. But periodic tragedies have blighted development of such treatments.
In 1999, 18-year-old Jesse Gelsinger of Arizona died while participating in a gene therapy trial. He died from multiple organ failures four days after starting the treatment, and investigators believe a severe immune response to the modified virus used in the trial led to his death.
The next blow came in January 2003, when a seemingly successful gene therapy treatment being tested in France for the immune condition commonly known as "bubble baby syndrome" led to a child in the study developing a leukemia-like disorder. A similar condition had occurred in August 2002 in another child who received the gene therapy treatment.
But despite past tragedies, what all of the diseases for which gene therapy shows promise have in common is that they have few, if any, effective treatments available.
"The devastating progression of organ or joint destructive disease in autoimmune disease can justify aggressive trials including gene therapy, or biologic therapies," said Dr. Stephen Mitchell, professor of medicine and pediatrics at Georgetown University.
And because patients in these trials are often already sick from their conditions, determining the exact cause of death can be a challenge.
"People with [rheumatoid arthritis] are at increased risk of dying from heart attacks, for example, and causes of death unrelated to the clinical protocol need to be considered," Fox said.
Informed Consent Key
Regardless of the cause, physicians agreed that the FDA's action is warranted.
"I agree that the FDA has acted appropriately to suspend this trial for the time being, until much more is understood about what happened," Fox said.
And Dr. Robert Yood, chief of rheumatology at Fallon Clinic, said the case underscores the potential problems that patients should consider before enrolling in a clinical trial.
"My reaction to the announcement is that anyone considering an experimental treatment for any medical problem must be informed of all known and potential risks and benefits and then make an informed decision about participation," Yood said.
"It is only through experimental trials that we advance in medicine. I am pleased that the FDA is reacting quickly to this particular issue and halting the trial until more is known."