Gelsinger’s death unleashed a mountain of scrutiny from the press and regulatory agencies. The Food and Drug Administration temporarily suspended two other studies using the same viral vehicle— adenovirus— that was used to deliver Gelsinger’s therapy. (Despite the similar name, adenovirus is very different from AAV.) Within months, the agency issued more stringent regulations on gene therapy clinical trials and the University of Pennsylvania (Penn) stopped all clinical trials at its Institute for Human Gene Therapy.

High’s hemophilia trial at Children’s Hospital, just down the road, used the AAV vector and was not delayed or shut down. Still, she says her work was affected in a broader sense. “It raised questions about the safety of gene therapy, and that had broad ramifications for the field,” she says. “It reduced the interest of pharmaceutical companies in pursuing gene therapy and heightened the perception that it was somehow dangerous.”

In the summer of 2001, High and Kay began a trial in which they injected factor IX into the liver of volunteers with hemophilia B. One participant, a 31-year-old man, had a baffling reaction. At first, the therapy worked exactly as it had in dogs: levels of clotting protein in his blood rose dramatically. But after four weeks, his factor IX levels dropped, while liver enzymes—a sign of liver injury—began to rise. By 12 weeks, his enzyme levels were back to normal, and he had no detectable factor IX in his blood.

The liver enzymes were a sign that the man’s immune system was killing all the cells that had received the new gene. As High and Kay later figured out, the patient’s immune system was reacting not to the new gene itself but to proteins, called capsids, that make up the shell of the AAV vehicle (known as a vector).

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“This was totally unexpected,” says Kay, now professor of pediatrics and genetics at Stanford. “There had been tests in dogs, monkeys, rabbits, rodents—nobody had seen this response in animals.”

After hearing the news, Avigen, the California biotech company that was providing High with AAV vector, pulled out of the research. In short order, High convinced her hospital’s leadership to build its own multimillion dollar, industry-grade vector manufacturing facility. It was up and running by the summer of 2005, and two years later the National Institutes of Health chose the facility to be the sole provider of all the AAV clinical trials it funded.

With an ample supply of AAV, High extended her work to other diseases. For years, she had wanted to collaborate with one of her Penn colleagues, ophthalmologist Jean Bennett, who she had gotten to know because their daughters ran on the same track team. Bennett had used AAV gene therapy on dogs with LCA, and all of them showed improved vision. High had tried to convince Avigen to begin an LCA clinical trial, but the company did not want to invest in such a rare disease.

With the new AAV manufacturing facility, High and Bennett could do it themselves. “Jean had done 35 dogs—it was clear that it worked,” High says. It was time to test it on people.

Seeing success

LCA is an untreatable group of diseases that crop up in about 1 in 80,000 people. The condition is caused by mutations in any of 13 known genes, including RPE65, which leads to the breakdown of cells in the retina, the light-sensing film that lines the back of the eye. (See sidebar, “RPE65: A Blinding Gene.”)

“These kinds of inherited retinal degenerations are just devastating—patients end up blind at a very young age,” notes Joan Miller, chair of the ophthalmology department at Harvard Medical School. Although some patients benefit from implantation of artificial retinas, “it would just be wonderful to restore a more natural vision to these patients,” she says.

After the disappointing hemophilia trials, High began to brainstorm ways to avoid the body’s immune response to gene therapy. The eye, she thought, might be an ideal spot: it’s a small and contained area—it would need only a small amount of AAV—and it is relatively easy for surgeons to access. The eye is also somewhat isolated from the peripheral immune system.

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