As the US Food and Drug Administration prepares to investigate the death of a patient in a phase I/II gene therapy trial for inflammatory arthritis, researchers in the field say the treatment's delivery vector, an adeno-associated virus (AAV), was unlikely to be the culprit.
"Vectors in this class have been used on hundreds of patients over the last 12 years, and are not associated with acute toxicity," said Terence Flotte of the University of Massachusetts Medical School in Worcester. Flotte has been a principal investigator in several clinical trials of AAV-based gene therapy, but is not associated with the trial in question. "I've never seen anything like this," he told The Scientist. "Whatever this is, it's unusual."
"The AAV vectors in themselves are unlikely to cause inflammation or cell damage," agreed Theodore Friedmann of the University of California, San Diego, previous president of the American Society of Gene Therapy. Although he cautioned against speculating in the absence of clinical data, Friedmann noted that the transgene the vector encoded could have caused the patient's reaction. "It's a powerful transgene," said Friedmann. "It might have induced a massive immune response of some sort."
Mark Kay of the Stanford University School of Medicine in Palo Alto, Calif., cited the excellent safety record adeno-associated viruses had both in animal and human studies. Kay, who has led trials that used these vectors, said however that in the present case he did not rule out the possibility of an acute immunological response to the AAV itself.
The FDA placed the trial on hold after the company sponsoring it, Targeted Genetics of Seattle, told the agency on July 20 that the patient had suffered a serious adverse event in response to the treatment. The patient died on July 24.
In the trial, the AAV vector delivered a transgene encoding the receptor for tumor necrosis factor (TNF)-alpha, a cytokine that causes joint swelling in arthritis patients. The receptor, secreted by the target cells, binds to TNF-alpha, to reduce inflammation and protect the joint.
Usually prescribed for autoimmune conditions such as rheumatoid arthritis, the TNF-alpha receptor works by suppressing the immune system. But the protein could also have opened the door to an infection, suggested Flotte.
According to a July 28 article in the Washington Post, the trial had raised safety concerns when it was proposed in 2003, including the fear that the viruses might spread from the joint to the whole body. Reviewers appointed by the National Institutes of Health's Recombinant DNA Activities Committee also questioned the usefulness of the study, since animal data had showed only a limited value for the therapy. However, the trial was eventually approved and progressed without serious side effects, according to a company official quoted by the Post.
In 1999, teenager Jesse Gelsinger died of multiple organ failure four days after getting gene therapy for a genetic liver disease. That vector, an adenovirus, was proved to be the direct cause of death. Since then, however, adenoviruses have been used in several trials without such incidents.
Adeno-associated viruses, also used in about a half-a-dozen ongoing gene therapy clinical trials, are thought to be safer than adenoviruses or retroviruses because they lack viral coding sequences in their genome and do not replicate.
Since the trial started in October 2005, 127 patients have received an initial injection of either the active drug or the placebo, according to Targeted Genetics. The patient's death came after getting a second injection, which contained the active drug, but the company has not disclosed whether his or her first injection was an active dose or a placebo...