The e-mail arrived just before Christmas. It was from an Italian ophthalmologist. “We want to share a very great emotion with you,” she wrote. One of her patients, a child, had gone to the countryside with his parents about 10 days before. The boy had been born with Leber’s congenital amaurosis, an inherited eye disease that had made him blind. Outside on one clear night, “he looked up at the sky and asked his mother what those little white spots were,” the doctor wrote. “He saw the stars for the first time in his life!”
These are the kinds of stories Jean Bennett has almost gotten used to receiving. The F.M. Kirby Professor of Ophthalmology and Cell and Developmental Biology is among the leaders of an international research team that has produced one of the most striking successes to date in clinical gene therapy. Since October 2007, they have given a dozen Leber’s patients an experimental treatment for the disease, which previously had no cure. The treatment has proven durable. Late last year, they reported in the Lancet that all of the patients had shown sustained improvement in vision, with the most substantial gains coming in children. Their eyesight did not jump all the way to normal levels—and the procedure was only done on one eye—but for some the difference is remarkable. Kids who had been utterly stymied by a simple standardized obstacle course can now zip right through it using their newly improved eye.
“Now, some of these kids are no longer legally blind,” says Bennett. “We’ve actually had to argue with support-service providers so that those services don’t get yanked away—the large-print books, the Braille lessons,” just in case there are reversals down the road.
The path to come this far has been arduous. It began with a blind dog named Lancelot, a four-year-old Briard sheepdog mix that suffered from a similar affliction. After being injected in the retina with an adeno-associated virus (AAV) engineered to deliver functional copies of a gene it lacked, Lancelot gained sight [“Gazetteer,” Mar|Apr 2005]. It only required a single procedure. As other dogs followed suit, a pattern emerged: the younger the animal, the more effective the therapy. The cure also proved to be long-lasting—six years later, Nature Genetics named still-sighted Lancelot its October “Mutant of the Month”—but that was no guarantee that it would work as smoothly in humans.
The leap to a human trial was a big one, says Katherine High, a professor of pediatrics based at Children’s Hospital of Philadelphia (CHOP) who was instrumental in bringing it about. “This was the first gene therapy trial that included pediatric patients with a nonlethal disease.”
High, Bennett, and others felt that the potential benefit far outweighed the risk. Yet persuading all the safety, ethics, and oversight committees, including a make-or-break hearing before the federal Recombinant DNA Advisory Committee, was an ordeal. After the 1999 death of Jesse Gelsinger in a gene therapy trial at Penn [“Gazetteer,” Nov|Dec 1999], “the safety ratchet went way up, especially at Penn,” says Bennett.
“I think that did improve the way we did things,” she adds. “But there are lots of bureaucratic obstacles that could serve as roadblocks to other researchers. I don’t know that I’d have the energy to go through it again.”
Winning approval was only one of many challenges. Avigen, the biotech company that had initially produced the AAV vectors critical to the procedure, pulled the plug on that part of its business. The firm had hoped their investment would pay off in the form of a gene therapy treatment for hemophilia, but those trials—which had showed promise in dogs—had proven frustrating in humans, where immune responses to the agent have yet to be overcome. Injecting it into the eye, where it wouldn’t come into contact with the blood supply and a far lower dose would do, seemed more promising. But Leber’s is very rare. It afflicts about 450 Americans—four or five babies a year are born with it, which hardly supports a sustainable business model.
So the work fell to the researchers. In Bennett’s lab, Jeannette Bennicelli Gr’92 cloned the gene that would be inserted into the virus. Fraser Wright, a research associate professor of pathology and laboratory medicine based at CHOP, turned that into a clinical-grade vector. Associate professor of ophthalmology Albert Maguire performed all the injections. Others directed regulatory compliance and coordinated the clinical care.
“Success in this kind of endeavor depends on having people with a wide range of skill sets,” High emphasizes. “You have to do every single thing right. I think we have some of the best people in the world on this team, and that’s why it worked.”
As in the dog trials, the one-time gene therapy treatment in humans was most effective on the youngest patients. For this round, subjects were no younger than eight years old, an age when they are deemed able to understand risk-reward tradeoffs explained in plain language. Going forward, Bennett hopes to extend the trial to children as young as three, and to begin operating on both eyes. (Any younger, and the rapidly growing eyeball makes the injection procedure increasingly tricky.)
In the meantime, she can probably look forward to more letters like the one that came before Christmas. They don’t get old. “When this happened for Lancelot, I was overjoyed,” she remembers. “It was hard to believe. We repeated the tests over and over to make sure. To see this in a child, though, it’s so emotional. It makes me want to cry when I see these kids.”
—T.P.