Stop the Bleeding: Can Gene Therapy Finally Cure Hemophilia?

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Recombinate, from Baxter, approved by the FDA in 1992. These drugs completely changed hemophilia treatment. Not only did they end the risk of contaminated blood, they also paved the way for preventative treatment.

“Now you have teenagers [who] don’t remember ever having a bleed,” says Katherine High, the president and chief scientific officer of Spark Therapeutics (NASDAQ: ONCE), the former director of the Center for Cellular and Molecular Therapeutics at the Children’s Hospital in Philadelphia, and a world-renowned hematologist.

For the roughly 20,000 patients with hemophilia A in the U.S., and the 3,000 or so with hemophilia B, it’s become a chronic, manageable condition, albeit still stressful and expensive to treat.

About 60 percent of the hemophilia population has severe disease, according to the National Hemophilia Foundation. They have less than 1 percent of the necessary clotting factor in their blood, and so they have more bleeds and need bi- or tri-weekly infusions. Milder cases bleed and need treatment less often.

A few companies are working on incremental improvements to the protein replacement drugs, with versions meant to be used once a week or less, or that aim to help patients whose immune systems won’t let them take current therapies. Alnylam Pharmaceuticals (NASDAQ: ALNY) is developing an RNA interference drug meant to be used even less often.

Katherine High

Katherine High

Beyond those improvements, gene therapy is shooting for long lasting solutions, perhaps even “one shot” cures. That’s the goal for many gene therapies, of course, not just in hemophilia. But the fact that even 30 years ago, hemophilia seemed to be the perfect application for gene therapy—and is still years away—speaks volumes about how hard the technology has been to harness.

For a long time, gene therapy seemed like science fiction. Microscopic viruses you’d think are dangerous are genetically engineered and used as little delivery vehicles, or “vectors.” Those vehicles are then packed with specific genetic instructions: go to this location and produce this protein. Or even, go to this stem cell and change its DNA, so every little baby cell that comes out afterward carries these genetic instructions too.

The promise is enormous. Find a disease you understand genetically—say, one known to be caused by a single faulty or missing gene—and engineer a long-lasting fix. Dozens of startups burst onto the scene in the 1990s, but they soon ran into technical challenges, especially around the viral delivery vehicles.

“It took time to figure out which vector systems are either the most easily used, or easy to make, or safest,” says Barrie Carter, the vice president who oversees gene therapy at BioMarin Pharmaceutical (NASDAQ: BMRN).

This was true in hemophilia, too. The disease has always been an ideal target for a gene therapy for a number of reasons. It’s monogenic (caused by a single mutation). It’s recessive (to fix it, a gene has to be added, rather than knocked out). And restoring only a little expression—some 5 percent of a normal person’s level of Factor VIII or IX—has a dramatic effect.

Barrie Carter

Barrie Carter

All those effects are easy to measure with a simple blood test. Along with cystic fibrosis, hemophilia was one of the first diseases tested with gene therapy. It was so ideal, in fact, that the pressure to use gene therapy became enormous. As The Scientist wrote back in 1999, “If gene therapy doesn’t work in hemophilia models, in what disease model will it work?”

In the late ’90s, the first wave of hemophilia gene therapy trials were beginning. High led one of the groups involved; she collaborated with an Alameda, CA-based gene therapy startup, Avigen.

High and her colleagues hadn’t focused on any specific technology. For viral vectors, “I tried everything,” says High, including retroviruses and adenoviruses, which are now largely antiquated delivery vectors due to safety and other problems.

According to Wilson, retrovirus wasn’t useful for hemophilia. It wouldn’t get into the liver, the body’s clotting factor production plant. And adenovirus, while adept at targeting liver cells and expressing genes there, wouldn’t produce a lasting effect. Worse, it threatened to set off a potentially dangerous immune response.

That threat became reality in 1999, when an 18-year-old Arizona teenager named Jesse Gelsinger became sick and died in a trial co-led by Wilson at UPenn. Gelsinger had a rare genetic disease of the liver called ornithine transcarbamylase deficiency, typically associated with infants, but he wasn’t sick. His condition was controlled with a restrictive diet and several drugs. The trial was to test the safety of a gene therapy that might ultimately benefit sick babies, and as the New York Times wrote in 1999, Gelsinger had volunteered knowing he wouldn’t benefit. But he paid the ultimate price. The gene therapy, delivered via adenovirus, triggered a wild immune system attack. He became jaundiced, suffered massive blood clots, and several organs failed. He died four days after treatment.

Wilson was soon at the center of a public and legal maelstrom. The FDA launched an investigation and suspended the trial, and later, the rest of UPenn’s gene therapy studies. Wilson became mired in lawsuits. Questions emerged about data that the investigators hadn’t initially reported from their research, including the fact that some monkeys were killed by these gene therapies in early testing. Wilson was also under fire for his ties to Genovo, the biotech that was funding much of UPenn’s gene therapy work (but not the Gelsinger study). Wilson founded Genovo in 1992, and both he and UPenn had an equity stake in the company.

“I was highly criticized, and under attack,” Wilson says. (Many years later, Wilson would write an editorial recounting the mistakes made, and lessons learned from the study, in Molecular Genetics and Metabolism.)

The damage reverberated through gene therapy, and companies in the field went into damage-control mode. Carter remembers how his former employer, Seattle’s Targeted Genetics, wrote a press release just to remind folks that it wasn’t using adenovirus. It got worse: Investors became skittish, the dot-com bubble popped, a slew of gene therapy startups crashed. In what seemed like a final blow to the field, four children in a French gene therapy study who were initially cured of a rare immune disorder later developed leukemia. One of them died in 2003.

Yet the maelstrom drowned out the fact that important progress was being made. A tool that’s become gene therapy’s most commonly used vector, the so-called “adeno-associated virus,” or AAV, was showing promise.

“This was the game changer,” Wilson says of AAV.

The name itself is a misnomer. AAV has nothing to do with adenovirus; its name came from … Next Page »

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One response to “Stop the Bleeding: Can Gene Therapy Finally Cure Hemophilia?”

  1. Barry L says:

    Should have been more complete color on what Sangamo Biosciences Hemo gene therapy is all about and how it is different.
    what the delay has been has not been divulged by either SHIRE or SANGAMO. My guess,,,,manufacturing in sufficient quantities to satisfy the demand. A “cure” is possible,,,,not if,,,,,WHEN