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."
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. "The clinical course that this individual experienced has, to our knowledge, never been seen as a consequence of exposure to adeno-associated viral (AAV) vectors," the company's president and chief executive officer H. Stewart Parker said in a statement
. The company did not return repeated phone calls requesting further information.
The FDA said in an online statement
that no similar adverse events in other current gene therapy trials have been reported. "However, as a precaution, the agency is further reviewing all ongoing trials involving any use of AAV," it said. The National Institutes of Health is collaborating with the agency to understand the scientific and safety implications of this event, and will present their findings at the September meeting of the NIH's Recombinant DNA Activities Committee, NIH spokesman Don Ralbovsky told The Scientist
Four other companies involved in gene therapy trials either did not respond to inquiries or refused comment. "There just isn't enough known yet for us to comment," said Channing Burke, spokesperson for Introgen Therapeutics
, an Austin, Texas-based company that has an ongoing gene therapy clinical trial for skin cancer using adenovirus as a vector. "We do not have an interest [in commenting] at this time," said Marion Ferguson, on behalf of Celladon Corporation
, a La Jolla, Calif.-based company with an ongoing clinical trial for AAV-based gene therapy for heart failure.
Links within this article:
A. Fischer and M. Cavazzana-Calvo, "Whither gene therapy?" The Scientist
, February 1, 2006.
J. Weitzman, "Gene therapy monkey business," The Scientist
, August 21, 2002.
American Society of Gene Therapy
J. F. Wilson, "Deconstructing Tumor Necrosis Factor," The Scientist
, May 1, 2000.
R. Weiss, "Suspended gene therapy test had drawn early questions," The Washington Post
, July 28, 2007.
Recombinant DNA Activities Committee
P. Smaglik, "Investigators Ponder What Went Wrong," The Scientist
, October 25, 1999.
Targeted Genetics statement, July 26, 2007.
FDA statement, July 26, 2007.