Researchers Katherine High (left) and Jean Bennett collaborated to move gene therapy for a blinding eye disorder from animal studies to human clinical trials, with promising results. This fall the researchers plan to launch a phase 3 trial, the last step to regulatory approval.

Today, researchers are tackling both problems by finding clever ways to deliver long-lasting, healthy genes without triggering a serious immune response. One promising approach is to repair a gene in the patient’s cells outside the body and then put the cells back after the gene has fully integrated into the genome. Another tactic is to tweak the vehicles that deliver the gene so that they aren’t as easily seen by the immune system.

Corey Haas navigating maze using only his untreated eye.
Video: Children’s Hospital of Philadelphia

Corey Haas navigating maze using only his treated eye.
Video: Children’s Hospital of Philadelphia

Then there’s the strategy behind the LCA trial: targeting parts of the body—such as the eye or brain—that are somewhat isolated from the immune soldiers in the blood. A leader of this study is Katherine High, a gene therapy pioneer and HHMI investigator at Children’s Hospital. High has her hands in many lines of gene therapy research, but so far the LCA trial has produced the most dramatic outcomes. At a conference in May 2011, her team announced the latest results: 3 of the original 12 patients have received the therapy in their second eye, and their vision has improved further. The researchers plan to launch a phase 3 trial—the last step on the long road to regulatory approval—this fall.

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After two decades in this controversial field, High has difficulty wrapping her head around this medical miracle. “It’s almost Biblical,” she says. “I still can’t quite believe that something like this could actually happen.”

Beyond dogs

High has been fascinated with the idea of gene therapy since she launched her first laboratory, at the University of North Carolina, in 1985. She had spent years pinpointing the genetic glitches responsible for bleeding disorders called hemophilias. Most of these mutations damaged clotting factors, enzymes that help the blood clot. “From there, it’s not a very far leap to ask if there’s a way we can use the gene to go into a person with hemophilia and correct their disease,” she says.

“It’s almost biblical. I still can’t believe that something like this could actually happen.”

Katherine High

Those were the glory days of gene therapy, when researchers were seeing their first successes in animal models and declaring that the treatment could one day cure thousands of genetic diseases. The first human clinical trial, launched in 1990, treated a rare immune deficiency, dubbed SCID, in a 4-year-old girl.

Researchers removed some of the girl’s blood, used a retrovirus to insert a healthy version of the broken gene into her white blood cells, and then infused the altered cells back into her body. The therapy seemed to work: four years later, the girl carried the healthy gene in half of her white blood cells. From 1989 to 1998, some 275 other gene transfer protocols were listed in U.S. regulatory registries, according to the NIH Office of Biotechnology Activities.

By the late 1990s, High’s team and a group at Stanford University, led by Mark Kay, had independently cured hemophilia B in dogs. Both groups used a new delivery method: they used part of a virus, called adeno-associated virus (AAV), and its outer shell to carry the factor IX gene, which codes for a clotting factor, into the dogs’ cells. AAVs were thought to be safer than retroviruses, which integrate themselves into the host’s genome and could potentially turn on cancer genes. In contrast, these modified AAVs almost always unload their genetic packages outside the host’s genome.

High and Kay collaborated to bring this therapy to human clinical trials. But eight months after they published their dog data, the field took a major hit. In 1999, a gene therapy trial for a rare metabolic disease at the University of Pennsylvania caused the death of an 18-year-old named Jesse Gelsinger.

Photos: High: Universitat Autònoma de Barcelona, Bennett: Daniel Burke Photography

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