For Jean Bennett and Albert Maguire, sharing a human brain in a neuroanatomy class stirred up a personal chemistry that produced a marriage and three kids. It led to a 25-year professional partnership as well, a collaboration that has yielded one of the first successful demonstrations of gene therapy in humans. The partners have restored much of the vision in patients who have a rare genetic form of severely impaired eyesight called Leber's congenital amaurosis, in which a mutated gene prevents the retina from manufacturing a nutrient vital to eye health. The technique eventually could be tried to treat macular degeneration.
The trickiest part for Bennett, a gene therapy researcher at the University of Pennsylvania School of Medicine, involved finding a virus that would deliver normal copies of the defective RPE65 gene to malfunctioning retinal cells—harmlessly. "We needed a virus that wouldn't replicate or cause a dangerous immune reaction," she says.
Manufacturing the gene-carrying virus and injecting that first patient was done next door at Children's Hospital of Philadelphia, where Maguire is a pediatric eye surgeon. It was, Maguire says, a bit terrifying. Foremost on his mind was Jesse Gelsinger, the 18-year-old who died a decade ago at the University of Pennsylvania hospital from a severe immune response during a gene therapy study of his metabolic disorder. But the surgeon ultimately forged ahead. "If my own son had had this disease, I would have let him be the first to have the treatment," says Maguire, "which to me is the highest level of stringency."
The treatment surpassed all expectations. The first three young adults treated—all legally blind, with vision worse than 20/200 and a small visual field, like looking down a gun barrel—saw so much more clearly that they could even read additional lines off an eye chart, according to the results published in last year's New England Journal of Medicine.
The patients, all of whom had only their worse eye injected, are thrilled, says Bennett. "Their main question is, 'Can I have my other eye injected?' " Most striking are the latest results, not yet published, for five children who have received the therapy over the past year. A 9-year-old Italian boy who once used a white cane, she says, now plays soccer for the first time in his life. And a video presented at a recent gene therapy meeting shows an 8-year-old American boy easily navigating an obstacle course of steps and hanging signs. A presurgery video shows him on a similar course completely bewildered, unable to take a step forward.
How long the inserted genes will last is uncertain, but the dog who got the first treatment (and whose silver-framed photo sits in Bennett's office), still has his vision nine years later. Bennett, who hears every day from those hoping for cures for their blindness, says the next step is to seek approval from the Food and Drug Administration so that more of the 3,000 Americans with Leber's can regain at least some of their sight. While gene therapy may still prove to be too tricky for metabolic disorders, its potential for other eye diseases appears promising. "I think we redeemed gene therapy, in a way," says Maguire.