GENEWATCH
 
GENE THERAPY TRIALS ON TRIAL
By Brandon Keim
 

On July 1, Jolee Mohr went boating with her family. The next day, the 36-year-old resident of Springfield, Illinois felt out-of-sorts, but well enough to go to work and then to the clinic where she was participating in a gene therapy clinical trial for rheumatoid arthritis.

Mohr received a shot of the therapy, her second. By afternoon of the next day she was feverish and vomiting. On July 24, with her liver failing, her body septic from an out-of-control fungal infection, and a football-sized blood clot nestled in her abdomen, she died.

What happened? Nobody is sure.

The therapy Mohr received was called tgAAC94, manufactured by Seattle-based Targeted Genetics, a small biotech company with its hopes pinned on that therapy and an experimental AIDS vaccine. To deliver a gene that would prevent her knee from producing arthritis-inflaming proteins, the company used what is known as an adeno-associated virus. These viruses had not caused problems for other researchers working on animals or in early-stage clinical trials.

When the National Institutes of Health's Recombinant DNA Advisory Committee gathered in mid-October to discuss Mohr's death, they were able to determine that the injection she received wasn't contaminated. The virus in question - which had been modified to prevent replication - hadn't spread to other parts of her body, nor did its DNA jump into an already-existing virus, spreading the new gene into other parts of her body and provoking a deadly immune response. The committee also said that a herpes virus for which she had recently received treatment did not cause her death.

But though the committee was able to rule out these culprits and none of the other 120 people involved in the trial experienced anything similar to Mohr's reaction, neither could they absolve the therapy. There was a giant hematoma in Mohr's stomach, but her blood didn't otherwise seem to have clotting problems. And while the fast-spreading histoplasmosis infection that wracked her body was a known side effect of the immunosuppressant arthritis drugs she was already taking, it could have been exacerbated by the therapy.

In short, the nation's finest gene therapy minds can't tell if Mohr's therapy killed her. They might never know. But whatever its cause, there are still lessons to be learned from the tragedy.

Regardless of the cause of death, the fact remains that the trial was not aimed at helping severely ill people. Rheumatoid arthritis can be a painful, crippling condition, but the study recruited people in whom the disease had progressed only to a moderate stage. With the help of drugs, Mohr led an active life. Until gene therapies can be better controlled, or in early-stage trials, it may be advisable for regulators to limit testing to severely ill people in whom other treatments have failed.

Meanwhile, though Mohr's trial was Phase I/II - i.e., intended to determine whether or not the therapy was safe, rather than whether it was effective - it was designed in a way that made it hard to tell: many of the people were, like Mohr, taking immune system-suppressing drugs that caused, at a systemic level, the same reaction that tgAAC94 was supposed to produce in a single location.

Neither did the doctors hired by the company appear to have been adequately trained to administer the therapy. That Mohr was not feeling well when she arrived at the clinic on July 2 should have been a warning sign to delay the shots until she was healthy.

There are also concerns about how the study was portrayed to Mohr. While her informed consent document was clearer about risks than that signed by Jesse Gelsinger, who died during a gene therapy trial in 1999, some bioethicists say the risk of death should have been made more prominent, rather than mentioned halfway through the 15-page document.

Also, the doctor who recruited Mohr was part of the study - something that could have affected how he portrayed it. According to Mohr's husband, she was under the impression that the treatment was supposed to cure her. Contributing to this impression may have been the timing of the shots, in that the second one was supposed to be given after a flareup of her symptoms, rather than at a set date.

Finally, in part because the FDA's requirements for reporting adverse effects during gene therapy trials are ambiguous, and because Mohr's doctor was initially reluctant to blame her decline on the therapy, the FDA wasn't told of Mohr's condition until two weeks after the injection, by which point she was in critical condition. That constitutes a two-week window during which the trial continued when it shouldn't have - and it wasn't until Mohr arrived at the University of Chicago that the biological samples necessary to rigorously analyze the progression of her disease were taken.

 

GOING FORWARD

So what should be made of all this? As mentioned before, doctors still don't know whether the therapy killed Jolee Mohr. Even if it had, her death wouldn't be reason to abandon the field. That the examples given of gene therapy's unpredictability - Jesse Gelsinger in 1999, three children who developed leukemia during another trial in 2003 - are always the same is telling. Given the thousands of people who've been involved in gene therapy trials, it seems there's a double standard at work. Had these deaths occurred in trials for standard pharmaceuticals, they would not likely have prompted such an outcry.

However, it is undeniable that there were serious problems in Mohr's trial - its inclusion of people taking other drugs with similar mechanisms, the lack of instruction given to clinicians, its unjustified presentation as a cure, and finally the trial's focus on people in whom arthritis was neither disabling nor unresponsive to other, better-understood treatments. Jolee Mohr never should have been a part of this trial to begin with.

Thankfully, these are all problems that can be solved. There are no villains here, just mistakes, degrees of ambiguity and oversights that can be anticipated. Federal regulators and institutional review boards can pay more attention to trial designs, insisting that they be limited to severe conditions - which the vast majority of trials in fact target - until the therapies are better understood. Regulators can make sure that people understand the possible risks of participating, and that doctors are careful about giving the therapy and attentive to the possibility of side effects.

Such increased oversight may strike some researchers as unnecessarily onerous. But given the attention that gene therapy receives, it is not only ethical but practical. Another case like Jolee Mohr's could discourage researchers, investors and people who might someday benefit from a form of gene therapy abandoned before it could succeed.

Brandon Keim is a former CRG communications director. He currently writes for Wired News.


 
 
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