Courtesy of Penn Medicine Department of Communications

Rewriting Life

The doctor responsible for gene therapy’s greatest setback is sounding a new alarm

Toxic effects seen in animals raise questions about new gene therapies for children.

An influential scientist involved in gene therapy’s biggest setback, the death of a study volunteer 19 years ago, has issued a surprise warning over the dangers of the gene-replacement technique.

James Wilson of the University of Pennsylvania reported this week that monkeys and pigs given super-high doses of gene therapy died or suffered disturbing behavioral changes.

“What is remarkable is we have not seen it before,” says Wilson. “We were surprised but shouldn’t have been. If you push the dose of anything high enough, you are going to see toxicity.”

The warning comes amidst a scramble by three companies—Sarepta Therapeutics, Pfizer, and Solid Biosciences—to be the first to use the technique to cure muscular dystrophy. That disease strikes young boys, destroys their muscles, and kills them by their 20s.

To attack the disease, researchers replace patients’ damaged copies of a gene called dystrophin by introducing viral particles that carry a correct copy. Reaching the countless muscle cells in a boy’s body requires extremely high doses of these particles—400 trillion or more per pound of body weight.

That’s where the danger could come in, says Wilson. At those doses, he says, his team found that two different viruses caused extreme and sudden immunological effects, including damage to the liver and blood vessels.

The report set stock prices of gene-therapy companies tumbling. The general type of virus implicated, called an AAV, is widely used and considered safe. More than 2,000 people have been treated with AAVs, which have been used in successful tests of gene-therapy treatments for hemophilia and blindness.

Thanks to those successes, gene therapy has been racing forward, building toward ever more dramatic cures. The latest tests move into unknown territory because they involve much higher doses (which are needed to reach muscles or brain cells) and because the subjects are children.

R. Jude Samulski, who studies viral gene therapy at the University of North Carolina and is involved with Pfizer’s project, says that because Wilson’s viruses were slightly different from those being used in trials, it is not known whether his findings apply to the studies under way.

However, Samulski says the mixture of scientific ambition, technological advances, desperate patients, and potential financial windfalls could be combustible.

“It would be very naïve for our community to assume we won’t have toxic effects,” he says. “People get comfortable, saying, ‘Hey, let’s do it—there is nothing lose.’ Well, it’s out there waiting. But when it’s going to happen, why it’s going to happen—nobody knows.“

Gene-therapy winter

The animals’ deaths from acute immune responses were eerily reminiscent of the 1999 death of Jesse Gelsinger, a volunteer in one of Wilson’s trials at Penn.

That death cast a pall over gene therapy and put trials on hold; Wilson was criticized for ignoring danger signs seen in earlier monkey tests. But he rose back to prominence, in part for his role in developing the safer AAVs.

Wilson’s latest concerns started coming to light in mid-January in connection with the IPO of Solid Biosciences, based in Cambridge, Massachusetts.

Just days before the IPO, Wilson suddenly resigned from his position as a scientific advisor to the company, naming unspecified concerns over high-dose gene therapy as the reason. Solid Biosciences then surprised investors by revealing that the US Food and Drug Administration had put a hold on part of its planned study on boys, citing questions about its ability to manufacture the high doses.

Despite the road bumps, the IPO was successful and the company raised more than $125 million. Solid declined to comment for this story.

Toxic findings

The concerns that caused Wilson to resign now appear to be, at least partly, those detailed in his new report, published January 30 in the journal Human Gene Therapy. He would not say whether Penn had alerted the FDA and the European Medicines Agency about his results before submitting them for publication.

The animals in Wilson’s studies had large doses of virus introduced directly into their bloodstreams, a procedure that takes only 10 minutes. Two monkeys died, and several pigs suffered damage to their nervous systems. One lost the ability to stand and was euthanized.

Essentially any drug becomes toxic if too much is given, but this is the first time that limit has been detected for the popular and widely employed gene-therapy viruses.

“I think the message is that for certain forms of gene therapy, and certain approaches to gene therapy, there may be situations in which we find dose-limiting toxicity,” says Wilson.

Studies of the extra-high doses have only recently begun. Among them, Wilson said in his paper, are the one initiated by Solid Biosciences as well as a study at Nationwide Children’s Hospital, in Columbus, Ohio, where at least 15 infants got megadoses in a successful effort to treat a different disorder, spinal muscular atrophy.

That study has been hailed as a major step forward for one-time gene-therapy treatments. Since spinal muscular atrophy is fatal by age two, parents and doctors are willing to take increased risks.

Wilson’s paper, however, suggests that less serious side effects seen in the Nationwide study could mean doctors are on the doorstep of the kind of accident that could stop progress on gene-therapy treatments in general.