Stop the Bleeding: Can Gene Therapy Finally Cure Hemophilia?

Stop the Bleeding: Can Gene Therapy Finally Cure Hemophilia?

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scientists who discovered it on adenovirus lab preparations in the 1960s. It was smaller than adenovirus, and had no known role in any disease. Scientists made the first AAV vectors in 1984; the first AAV clinical trials, in cystic fibrosis, came in 1994 (run by Targeted Genetics). The first hemophilia trials came five years later, run by Avigen and High’s group at the CHOP.

While nearly all for-profit activity in gene therapy ground to a halt after the bubble crash and trial deaths, High, Wilson, and others not only kept the field afloat, but helped make the advances that have led to the current hemophilia race.

Wilson’s path forward took a particularly odd turn. Shaken up and in no position to compete for NIH grant money after the Gelsinger fiasco, he went to an old mentor, Tachi Yamada, then the chief scientific officer of SmithKline-Beecham (now GlaxoSmithKline).

Wilson wanted counsel, but he got more. “He said ‘I believe in you. I think you can do it. So how much money do you need?’” Wilson recalls. “I said ‘What do you mean?’ He said: [SmithKline-Beecham] would love to fund you in this endeavor.’”

James Wilson

James Wilson

Wilson asked for $3 million to $4 million a year, Yamada made a phone call, and that was that. No grant application, no competition, no angst. Wilson got about $40 million from the big British drug maker over the next several years and went “subterranean.” He eschewed scientific lectures, he stayed away from awards banquets, and he avoided the press. “It was all about doing science,” he says.

High had her own brush with disaster. In the Avigen hemophilia study, a patient given an AAV gene therapy produced Factor IX for four weeks but then lost it, and enzymes in his liver spiked, which in some cases can mean inflammation or damage to the liver. In a post-Gelsinger world, with so many unknowns about gene therapy technology, that was particularly scary. Worse, High hadn’t seen this in animal studies; she was at a loss. “We didn’t know what was happening,” she says. “I still remember that as one of the most challenging times of my career. There was nobody to ask, no animal data to fall back on.”

The patient was being treated in Australia. High could only listen helplessly as reports came in twice a week. Slowly, to her relief, the patient’s liver function normalized, and he was never in mortal danger. But the FDA, on high alert after the Gelsinger case, put the trial on hold. When the trial resumed, it happened again to another patient.

Neither case was fatal, but Avigen had had enough and pulled out of gene therapy altogether.

That was a big problem: Avigen was making High’s vectors. So she went to CHOP CEO Steven Altschuler and pleaded for the hospital to set up, in-house, a clinical grade manufacturing facility. The decision wasn’t easy; the Gelsinger case was in litigation, and the sentiment around gene therapy was understandably negative. But High was adamant these problems could be solved. “I know a showstopper if I see one; there’s not a showstopper here,” she recalls telling Altschuler. “It’s always been my belief that if you can transplant an organ, you can transplant a gene.”

After a few days of thought, Altschuler sided with High, on one condition: she had to work on other genetic diseases too, not just hemophilia. The CHOP not only built manufacturing, it created an entire center for gene therapy. High recruited folks from Avigen, and one of them, Fraser Wright (now Spark’s chief technology officer), applied for and won an NIH contract to be the only federally-funded AAV manufacturing facility in the country.

“They had to basically build their own infrastructure to be able to manufacture and run their own clinical studies,” says Ken Mills, a former diagnostics executive who co-founded RegenX with Wilson (and through RegenX has also invested in Dimension Therapeutics).

The CHOP work led to a breakthrough for the problem that shut down the Avigen trial. Because most people have been infected at one point or another with the AAV variant High was using, the immune system recognized it, attacked it, and shut it down. That’s why enzymes in these patients’ livers were spiking. High began thinking of ways to combat this problem, like using steroids to stifle the immune response.

“Sometimes the way that I feel about my career is that I just keep walking along a list of problems, working my way to the end, and then starting back over again getting more refined solutions,” says High with a chuckle.

She also found a home for that variant—called AAV2—as a treatment for a childhood blindness called inherited retinal dystrophy. There was a sweet spot in the back of the eye, where the immune system couldn’t wash it out, and it only needed to have a small effect in a tiny area. That program, now known as SPK-RPE65—it inserts a healthy version of the RPE65 gene—led to the creation of Spark.

“That caused people to stand up and say, ‘Gee, these vectors can really do something that is clinically important,’” says BioMarin’s Carter.

With its SmithKline-Beecham funding, meanwhile, Wilson’s group stayed together and focused on finding better AAV vectors. “We became virus hunters,” he says, isolating AAVs from “whatever source we could”—monkeys, apes, humans—and screening them for differences.

They found about 150 variations, which would be named AAV7, 8, 9, and so on, and started turning them into vectors. (Wilson and Mills would later cut a deal with GSK for an exclusive license to these vectors to form RegenX.)

This flurry of vector work in Wilson’s lab is also part of the hemophilia story. One of Wilson’s post-docs, Lili Wang, had been studying hemophilia B using AAV2 in dogs, but the levels of Factor IX it produced were too low. Wang then tried one of the new variations, AAV8, in the same dogs, and the results were “20 fold higher,” says Wilson.

AAV8 also wasn’t as prevalent in humans as AAV2; perhaps it wouldn’t trigger immune system alarms. Wang and Wilson co-authored a 2005 paper in the journal Blood to share the results.

During this time, Wilson encouraged academics to use these vectors for their own research. High was one of them. Another was a group split between St. Jude Children’s Research Hospital in Memphis, TN, and University College London who were intrigued by the UPenn dog study and wanted to try AAV8 for hemophilia in humans.

Wilson gave them access, and they ran a study with rousing results, which were published in the New England Journal of Medicine in 2011. The researchers—led by UCL’s Amit Nathwani—showed that an AAV8 gene therapy helped six patients with severe hemophilia B produce … Next Page »

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