Between October 2007 and June 2009, the five children and seven adults in High and Bennett’s eye study underwent a 90-minute surgery to receive the gene therapy. The surgeon, Albert Maguire (Bennett’s husband), had done all the canine eye surgeries in Bennett’s earlier work.

Maguire injected a tiny amount of liquid holding the AAV package into a pocket of space under the retina. The vector would migrate into retinal cells and release its DNA contents: the healthy RPE65 gene. The DNA would then invade the nucleus and be expressed just like a normal gene.

For three months after the surgery, the 12 patients returned to the hospital several times for various vision tests, from eye charts to measuring the range of peripheral vision to navigating floor mazes. All the participants showed improvement in at least one of the tests. Their pupils showed a 100-fold or greater response to light. Four patients are no longer classified as legally blind.

High is professorial and intense when she discusses the molecular tricks of gene therapy. But she gets emotional when talking about LCA patients. Her favorite anecdote concerns the oldest participant, 44-year-old Tami Morehouse, whose daughter is a star softball player. Before the treatment, Tami would sit in the bleachers at her daughter’s games, in near darkness, hanging on every word of a play-by-play from her husband.

“After she had this procedure, she was sitting in the stands one day. She couldn’t see the outlines of her daughter’s face, but she saw the person on third base steal home. And that was her daughter,” High says, tearing up. “It’s very, very hard to fully comprehend that kind of thing happening.”

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Tami's improvement is impressive, but the younger participants showed even better results. Corey, for instance, now age 10, can read the blackboard at school if he sits in the front row. He plays outfield on a Little League baseball team and rides his bike independently. “There are a lot of differences in colors now,” Corey says. “When I go outside, my pupils will shrink right down.”

At the same time as the Penn trials, research groups in London and Florida were doing similar AAV therapy for LCA. Patients in all three groups saw gains in vision after the treatment. And, perhaps best of all, none had an immune reaction to the therapy.

“The ophthalmology field was very excited because this was such a huge advance,” says Harvard’s Miller. The findings, which received a lot of media attention, also helped gene therapy’s reputation. “Gene therapy had taken a major hit before this,” Miller says. “So this [research] was a huge push for gene therapy of any kind.”

Evading the alarm system

There are dozens of viable approaches to gene therapy, and High has, at some point, worked on most of them. For example, the vector manufacturing facility at Children’s Hospital produces not only AAV viral vectors but also lentiviral vectors. Lentiviruses—retroviruses of which the most famous is HIV—work by quietly slipping their contents into the host’s genome, so that every time the host cell replicates, so does the virus. This is one reason why HIV is so destructive—and why lentiviral gene therapy has much promise.

Retroviruses were used in the first gene therapy trial and now, 20 years later, several groups are making headlines for treating blood diseases with the same approach. Researchers first harvest blood stem cells—which can give rise to any type of blood cell—from the patient’s bone marrow. In the lab, they mix the stem cells with a lentivirus that delivers a healthy version of the broken gene. Finally, patients receive an infusion of their own repaired stem cells. If all goes well, their daughter cells will carry working copies of the gene.

With this so-called ex vivo approach, “immunity is not a big issue,” notes Luigi Naldini, director of the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, who has worked on lentiviral vectors for 15 years. The lentivirus delivering the new gene is cleared away before the cells are infused back into the body, so the immune system has nothing to pounce on. “You prevent the alarm system from going off,” he says.

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