Philly’s Spark Therapeutics Is Revolutionizing Medicine

Spark president Kathy High. Her research, along with that of Jean Bennett, gives Spark big potential. | Photograph by Dave Moser

The dogs told her it would work, back in 2000.

Jean Bennett had been a gene-therapy researcher for two decades at that point, starting with a lab at the NIH. She began, as many scientists do, wanting to conquer her field in a big way, believing that if the genetic bases for gnarly diseases could be identified, they could be fixed. She picked Alzheimer’s. It wouldn’t, Bennett soon discovered, be quite that simple. Nothing in gene therapy, she would find, is simple.

Eventually Bennett would partner with another researcher working on genetic disease in the retina. This wasn’t a disease like Alzheimer’s, but more straightforward: a genetic defect identified; a healthy gene cloned in a lab, then delivered within a virus that would be surgically implanted. Yet developing the process took years of research. Bennett worked with mice and with rabbits, whose eyes are closer in size and shape to human eyes. She got hired by Penn in 1992 as a professor in ophthalmology; her husband, Al Maguire, an eye surgeon at Children’s Hospital, helped in her retinal research, wheeling large lasers between Penn and CHOP. Penn Med was a hotbed then of gene-therapy research, led by Jim Wilson, who’d been brought in by über-aggressive CEO Bill Kelley to build a cutting-edge lab with the best collection of genetic scientists, Jean Bennett believes, in the world.

Then, in 1999, disaster struck: An 18-year-old boy named Jesse Gelsinger died in a gene-­therapy trial overseen by Wilson, and suddenly the whole field came to something of a standstill.

Quietly, Jean Bennett carried on. She could still tap some NIH money, and Penn didn’t put the kibosh on her research. She also had a stroke of luck: A co-researcher at Penn told Bennett about a blind Swedish briard dog that had been bred to produce puppies who were also blind. Bennett tested them and found the problem was with RPE65, the retinal gene she’d end up working on. Al Maguire injected three four-month-old puppies in one eye.

The change was rapid. Bennett got a call two weeks later to come see the dogs. She raced over. They’d been hesitant, nervous, blind. Now they bounced down the halls, tracking where they were going by turning their heads, using their treated eyes. Bennett was soon playing tag and fetch with Lancelot and his siblings.

“It was crystal clear at that point it was going to work,” Bennett says. “We had to figure out how to do it to help children.”

But it would take almost a decade before Bennett could conduct trials on children. Christian Guardino was one of the kids who received a new RPE65. A couple days following his surgery in 2013, when his eye patch was removed and he opened his eye, Christian said, “Mom, Papa? Is that you?”

It worked. And then it took another four years for the FDA to say yes.

Spark Therapeutics was formed in 2013, in collaboration with CHOP, to develop and market gene therapies. Late last year, the FDA approved Spark’s Luxturna, the first gene therapy green-lighted in this country that targets a disease caused by mutation in a specific gene — the cure for the rare retinal disease that Jean Bennett has been working on for the better part of two decades. It marked a turning point for gene therapy, and perhaps for Philadelphia as a center for it. Biotech is having a moment here: Also last year, the FDA approved a game-changing personalized cell-therapy treatment for leukemia developed by researchers at Penn and CHOP and marketed by Novartis.

There’s a new vibe in Philadelphia. Jim Wilson, still considered one of the foremost gene-therapy researchers in the world and still running his research lab at Penn, laughs about how one of his students is already planning to launch his own company. “He hasn’t even started grad school yet,” Wilson says. But that’s the new paradigm: from the lab to the marketplace. Wilson says new companies are nipping at his heels, siphoning off his researchers. He continually gets calls from investors.

In late June, Penn revealed it would be investing up to $50 million in biotech firms, with the proviso that the companies’ headquarters remain in Philadelphia, which is the linchpin in making this region a major player in biotech. The venture capital and support systems for nascent companies have typically been elsewhere, especially in Northern California and Boston.

It’s an interesting time for biotech in Philadelphia, as we seem to risk fighting our own nature. Steve Altschuler, who ran CHOP from 2000 to 2015, says, “Penn is still very conservative.” That $50 million gambit might suggest otherwise. But Altschuler says Penn declined an investment role in Spark, and that overall, the local biotech scene is moving in “fits and starts.”

The science is here, at any rate: Jim Wilson estimates that there are at least 1,200 scientists in the area working on gene and cell therapy. The problem is that we’re now a couple of decades into a pattern of fundamental research being done in Philadelphia, then being lifted to Boston or the Bay Area to make medical products. Biotech players bemoan the lack of venture capital betting on this city. Wilson works with five gene therapy companies in some sort of advisory capacity; none are headquartered here.

Spark, firmly entrenching in West Philly, may be about to change that trend.

If it’s possible to be intense and goofy at the same time, Kathy High has it nailed. I ask the Spark Therapeutics president and head of R&D about frustration — about how long it takes to get anywhere in the gene therapy world. “The way I think about it,” High, 67, says, “we’re blazing a trail, and I may not make it. I may be like Moses and never see the Promised Land.” Then she smiles her impish smile: “Medical journal editors don’t like me, because I try to put everything in a paper so somebody coming along knows what to look for.”

High would like to rid the world of hemophilia, and she’s close to making serious inroads in that direction through a gene-therapy treatment Spark is testing. Spark is really her baby — she’s the big scientific brain behind it — and it was High who gave Jean Bennett’s gene therapy the big push to the FDA finish line.

High also came to Penn in 1992, when she was offered the opportunity to do research in the Bill Kelley era. Around that time, she partnered with Avigen, a biotech start-up in Northern California. Avigen eventually got out of gene therapy, in part due to the cloud over the field after Jesse Gelsinger’s death, so High needed help. In 2004, she went to Steve Altschuler at CHOP with a request: She wanted him to fund her research. She needed Altschuler to invest some serious money in order for her to make clinical-grade vector—the vehicle to deliver corrective genes to hemophiliacs — in his hospital. Really, though, she was asking for a much bigger commitment than that. She’d need facilities and have to recruit scientists and trial designers from industry.

“I expected him to say no,” High says. Since Jesse Gelsinger died during a Penn trial, it would be particularly difficult to overcome the fear of gene therapy here. Gelsinger suffered from a rare metabolic disorder that wasn’t life-threatening; after he was infused with corrective genes, he had a chain reaction of multiple-organ failure, the cause of which was never pinned down.

But Altschuler knew High and her work — he’d been chair of pediatrics at Penn Med before moving to CHOP — and he felt gene therapy had made advances in knowledge and technique. He was ready to make a bold move, though it was a gamble. “Sometimes you’re not 100 percent sure,” Altschuler says.

In fact, it took only a week or so for him to say yes. Altschuler moved fast partly because the top scientists High wanted to hire were going to get picked off by somebody else — the irony of the Gelsinger cloud was that underemployed first-rate talent was available. Altschuler committed $50 million to a clinical center High would run.

But he had a stipulation: Her clinical work couldn’t revolve around just hemophilia. Altschuler had to be able to sell to the CHOP board and patients’ families and the public that his investment would help, first and foremost, children, and hemophilia isn’t necessarily thought of as a children’s disease. “I wanted to be able to say that we’re taking on a platform that could impact all genetic diseases of childhood,” Altschuler says.

Enter Jean Bennett, curing a form of blindness that affects children. High knew Bennett and her work, and bringing her on board would meet Altschuler’s need.

“Kathy knocked on my office door,” Bennett recalls, “and said, ‘Jean, how would you like to run a clinical trial at CHOP for retinitis pigmentosa?’” — trials, that is, on children, not mice or rabbits. “I was stunned, but not so stunned that I didn’t answer yes in a thousandth of a millisecond.”

There were still some major hurdles on the way to getting the FDA on board. One was the FDA’s assumption that surgeons would want to correct both eyes at once, which required Bennett to do more work with dogs to test out any unforeseen risks with that approach. Another was proving that the treatment would have positive real-life consequences — sight tests in blind children didn’t provide the necessary data. So Bennett and her team came up with an obstacle course, first for dogs, later for children, to be navigated pre- and post-surgery.

Clinical tests on children began in 2007, and over the next several years, the results were stunning. Among the success stories was Christian Guardino, who’d spent his childhood honing his singing in part because of limitations with his sight. Last year, Guardino took America’s Got Talent by storm, and when Simon Cowell gave him a standing ovation, he had a clear-eyed view.

If Steve Altschuler took a leap of faith in supporting Jean Bennett’s and Kathy High’s research, he took another when it came to launching Spark as a business enterprise. In 2011, Altschuler tasked Jeff Marrazzo with walking the halls of CHOP, trying to identify research and brainstorms that might fly commercially. Marrazzo, now 40, had gotten to know Altschuler in 2006 while working on a dual Wharton/Harvard degree in business and public policy. He’d go on to work for a biotech start-up for a short period. Marrazzo is a businessman who, he says, “fell in love with science.”

Kathy High, it turned out, was the last of 25 CHOP scientists Jeff Marrazzo met with as he searched CHOP for commercial opportunities. As the story goes — perhaps embellished, perhaps not — a one-hour meeting turned into seven hours. Marrazzo’s wife kept texting; he was due home in New York.

“I’m with Kathy,” he texted back.

“Who’s Kathy?”

After the conversation, Marrazzo challenged Steve Altschuler to create a business with High. Though there was risk, the timing was right once again. Altschuler felt CHOP was at a financial crossroads. Post-’08 recession, it would need funding beyond clinical care and NIH or other government support, and Altschuler believed CHOP could make money from its intellectual property. Jean Bennett’s retinal therapy was going into phase three, the final push for FDA approval, which would require a sizeable investment. Kathy High’s progress with hemophilia B looked promising. And gene therapy in general was moving forward.

Meanwhile, Kathy High was getting calls from Big Pharma and from investors, who were more and more interested in what she was up to at CHOP. High was leery of pharmaceutical companies. “They really walked away from gene therapy 10 years ago” — in large part because of Jesse Gelsinger’s death. “I was a little afraid for any of my programs to go to Big Pharma,” she says. “If they have a bad year … ” High smiles, as if all the trials, literal and otherwise, of getting drugs to the marketplace to help children are simply part of a vast puzzle she finds intriguing. But that amusement really masks her fierceness. Gene therapy is her calling. “Talking to Jeff, I thought we could really be a company. As other companies were forming up, they were raiding us all the time.”

The real-world proof that the FDA demanded — how did Bennett’s treatment make an actual difference in the lives of children? — became a video that was shown to the CHOP board and investors: a child who was once blind, navigating an obstacle course with ease.

“It is biblical,” Penn’s Jim Wilson says. “The blind man can now see.”

CHOP committed $50 million, and Spark was launched.

Spark Therapeutics, as of early July, has 342 employees. At the moment, it occupies three spaces in West Philly as it renovates the one-block building just west of 30th Street Station that housed the Philadelphia Bulletin. That, says Jeff Marrazzo, now the CEO of Spark, will be home.

Spark went public in 2015; Steve Altschuler, now head of its board, says CHOP has reaped $300 million selling its stock in the company and still owns about 10 percent, worth an additional $300 million. It has been, to say the least, a good investment — one that Penn missed out on.

Luxturna, in treating a rare form of blindness, won’t be a big moneymaker; so far, post-FDA approval, Spark has provided treatment for nine patients, at $850,000 each. The company’s market value is really, at this point, a bet on Spark’s FDA approval for a hemophilia A gene-therapy treatment; the market for all hemophilia treatments is in the $10 billion range, Altschuler believes.

Finally, the Jesse Gelsinger tragedy has subsided as a bugbear for the risks of gene therapy. But there are still some thorny ethical issues to consider. Since gene therapy as a medical tool is so new, how Spark or any other company would get a treatment for hemophilia A to the developing world, for example, is a big unknown.

As far as the potential of genetic modification to make us better, faster, stronger, that’s not a question of if, but when: “People say we’ll just fix diseases — are you kidding me? People in Philly pay $70,000 to get their kids in the right nursery school,” says Arthur Caplan, a longtime bioethicist at Penn who now works at NYU. The good news is, we’re not there yet: “We won’t be tweaking up the music or math gene in the next 10 years. But it’s coming.”

At any rate, there’s plenty on our doorstep right now. “We’ve got three target tissues,” Kathy High says in answering what’s on Spark’s plate, “the retina, the liver, and the central nervous system.” Spark is targeting the liver for hemophilia and Pompe disease and the CNS for Batten disease. All of these procedures are gearing up for the long trek toward FDA approval. “Also,” says High, “we’re working on a program for Huntington’s” — that smile betrays her again — “but we haven’t disclosed the strategy.”

The potential remains vast, and there’s another unanswered question: Is Spark the tipping point for Philadelphia in the biotech world? No one knows. But here we are, poised, as this city often seems to be, at the starting line.

Published as “Seeing the Future” in the September 2018 issue of Philadelphia magazine.