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Biotechnology and health

Gene Therapy Is Curing Hemophilia

Spark Therapeutics is turning gene-therapy experiments into real drugs.

Earlier this spring, Bill Maurits sat in a waiting room in Philadelphia ready to have a trillion viruses dripped into his body through an I.V. “I was like, ‘Yeah, let’s go. I can’t wait,’” he says.

Maurits has hemophilia B, which means his body doesn’t produce enough factor IX, a protein that clots blood. He’s at risk for bleeding and his joints are damaged from all the bruises. Since he was 10, he’s depended on injections of “ridiculously expensive” replacement protein. Lately, his left ankle has been killing him.

In April Maurits, an engineering designer, joined a study in which he was dosed with viruses packed with a correct version of the gene that codes for factor IX. Today at the European Hematology Association’s meeting in Copenhagen, the Philadelphia company that ran the gene-therapy study, Spark Therapeutics, is presenting results on four patients, him included.

In all four, factor IX activity has reached about 30 percent of average. That’s enough to prevent bleeding when you get hit by a baseball or twist your ankle. It’s also been enough to let Maurits go without factor IX replacements since April. “There’s no other explanation than ‘It worked,’” says Maurits.

Sure, gene therapy has been tried before. What’s different is that Spark’s therapy so far appears to work well every time it’s attempted—a consistency that’s eluded previous efforts. “Right now this looks very close to being as good as it gets,” says Edward Tuddenham, a hematologist at University College London, who led a competing study and consults with some of Spark’s rivals.

The results are satisfying news for people like Maurits, as well as for scientists who’ve struggled for three decades to get gene therapy right. Two gene therapies for ultra-rare inherited disease are approved in Europe, including one cleared last month to treat severe immune deficiency.

But hemophilia could be the big one. It affects about one in 5,000 men (women are rarely affected). And there’s already a lucrative $10-billion-a-year market in blood factor replacements. “Curing hemophilia would be a signal to the marketplace that gene therapy has hit prime time,” says Eric Faulkner, who studies disruptive medicines at Evidera, a consultancy.

Only a larger study will reveal for sure whether Spark’s treatment proves out. “This is four subjects. We are going to need more,” says Katherine High, the hematologist who is Spark’s president and founder. “If you saw that in 40 subjects, then maybe … well, it’s very exciting.”

Spark does have competition. UniQure and Baxalta are both testing gene therapies for hemophilia B. And the drug company BioMarin is testing a genetic fix for hemophilia A, the more common type; it has reported results in eight patients, and Tuddenham calls them just as impressive as Spark’s. 

Some scientists say it’s too soon to declare success, since patients’ factor levels are still short of normal. “I wouldn’t say they’ve found the cure but this is the first time it looks good,” says Federico Mingozzi, a gene-therapy scientist at France’s INSERM research institute. “The true innovation is that they have really had a consistent result. I haven’t seen that before.”

Immune reaction

If gene therapy succeeds, hold on tight. One-time cures for devastating illnesses could command eye-popping prices of $1 million a dose, perhaps more. But it might be worth it and then some, says Mark Skinner, a lawyer and former president of the World Federation of Hemophilia. He says his severe case of hemophilia already costs $750,000 a year in drugs to treat.

Bill Maurits and his family visiting Niagara Falls two month after his hemophilia was treated with gene therapy.

MIT Technology Review met with High last week at Spark’s laboratories and offices in Philadelphia, where she described 30 years of research that led to the drug. It began in 1989 when High, then a professor, helped isolate the canine version of factor IX. Within a decade, she says, gene therapy was consistently curing dogs—more than 100 so far.

But attempts to treat people ran into trouble. In 2006, High showed that gene therapy increased factor IX in human patients. But the effect was undone by an immune reaction never seen in dogs. The patients’ corrected cells got attacked, and the effects, at first promising, wore off. “We didn’t know what was happening,” says High.

By 2010, researchers at University College London and St. Jude’s Hospital in Memphis, led by Tuddenham, had learned from High’s failure. They began using well-timed doses of immune-suppressing drugs to manage the effect. But the treatment wasn’t strong enough, even at high doses. Five patients ended up with about 5 percent of normal factor IX activity—an improvement still short of a cure.

Spark was formed in 2013, when High spun her gene-therapy research group out of Children’s Hospital of Philadelphia. By then drug giants were becoming interested in gene therapy again, and in 2014 Pfizer, which manufactures and sells factor IX protein under the trade name BeneFix, bought the right to commercialize Spark’s treatment if it is approved.

High says Spark needed to find a way to administer viruses in a dose too low to trigger the immune system, yet large enough to get factor IX levels way, way up.

The company started by redesigning a virus to take DNA straight to the liver, where factor IX is made. An unusual case in Italy provided another boost. A healthy young man turned up with a serious blood clot in his leg; he turned out to have a variant of factor IX that was hyperactive, causing 776 percent of normal clotting. Bad for him. But brilliant serendipity for High’s team, which seized on the hyperactive gene, called the Padua variant, as a way to produce stronger effects.

At Spark’s lab, High points down a gleaming white hallway lined with clean rooms where the viral particles are made. Close up, they're shaped like flexible dog toys covered with wobbly spikes. Spark can insert genes into them. Infused into a patient, they rush to liver cells and deposit the new DNA.

Finish line

Spark is also using gene therapy to treat a cause of inherited blindness, Leber’s congenital amaurosis, for which no treatment exists. The company will seek approval for that drug later this year, potentially making it the first gene therapy for an inherited disease to reach the market in the U.S.

But hemophilia could be a more clear-cut victory. Existing drugs offer an obvious standard to beat. And a fast, simple blood-clotting test can easily tell you if it’s working. “The best part of my day is telling Bill what his factor level is,” says Lindsey George, the doctor at Children’s Hospital who infused Maurits with Spark’s drug.

One measure of how well things are going: High says the FDA is concerned patients might produce too much factor IX. That would mean they’d have the same problem as the Padua man. “The regulatory agencies don’t want you to go above 100 percent,” she says. After a decade of attempting to get any effect at all, she says, “it’s amazing to think you could do too well.”

George does say one huge asterisk remains: about 40 percent of hemophiliacs can’t be helped yet. That’s because the type of virus used in this therapy is similar to one that naturally infects people. The result: many people have virus-grabbing antibodies in their blood that would intercept Spark’s treatment on its way to the liver. Such patients have been excluded from the study. “It's an obstacle to calling this an off-the-shelf treatment,” says George. High is working on ideas to overcome the problem, including releasing decoy viruses to soak up the antibodies.

Xavier Anguela, a Spark scientist, says if companies beat hemophilia they’ll quickly start working on many other rare diseases that can also be treated by adding genes to the liver—for instance, rare enzyme deficiencies like Fabry’s disease. “It’s only fair that Kathy crosses the finish line first,” says Anguela. “But for gene therapy, hemophilia isn’t even the finish line. It’s just the start.”

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