Gene Therapy in a New Light- page 3 | Science | Smithsonian
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Born with a disease that has robbed her eyesight, Alisha Bacoccini (being examined by surgeon Albert Maguire) is undergoing experimental gene therapy at the University of Pennsylvania. If she weren't legally blind, says the 20-year-old massage therapist, she would want to be a forensic scientist. (Stephen Voss)

Gene Therapy in a New Light

A husband-and-wife team's experimental genetic treatment for blindness is renewing hopes for a controversial field of medicine

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(Continued from page 2)

On the sidewalk outside her office, Bennett shows off one of the more than 50 dogs they have treated. Venus, a medium-size briard with brown, wiry hair, strains at her leash and would clearly like to race away, but she sits to let a visitor pet her. "When she came here, she couldn't see a thing. She would crouch in a corner or in a cage baring her teeth at people," Bennett says. That was a year ago, before the Bennett/Maguire team treated the then 1-year-old in both eyes with gene therapy. Though still night blind, Venus can now hop over obstacles strewn along a corridor and catch a tennis ball. "Her behavior was transformed," Bennett says. "She's seeing well in both eyes. She's a very happy dog."

When they first tried the treatment in people, Bennett and Maguire didn't expect their patients to improve as much as the dogs. For one thing, the doctors were testing safety first and used low doses of the virus and gene. And their first patients, all from an eye clinic in Italy that tests blind patients for genetic defects, were 26-year-old twins and a 19-year-old. By that age, LCA patients don't have much retinal tissue left. Most are completely blind by age 40.

Still, Bennett and Maguire didn't know what to expect when they treated the first patient, one of the twins. He was anesthetized, then Maguire made several small incisions and replaced the gel-like vitreous material in the man's eye with a salt solution so that Maguire could maneuver a needle through it more easily. Using a microscope, he threaded a hair-thin needle through the white of the eye until it touched the retina. He injected 150 microliters of a solution (a drop the size of a pea) that contained 15 billion copies of the AAV virus with the RPE65 gene. The virus is considered an extremely safe delivery mechanism—it can't replicate on its own, and it doesn't cause disease in humans.

All the same, that night "I didn't sleep at all," says Maguire, who was worried about an immune reaction. To his relief, there wasn't any.

Even though the dose was low, Bennett says the first time she looked at the young man's pupillometry data was "a Eureka moment"—his eye could sense more light. A few months after receiving the experimental therapy, all three patients were seeing more light. Two who could see only hand motions before could read three or four lines of an eye chart.

All three patients' eyesight is still improving, Bennett says. The 19-year-old, who has returned to Italy, no longer needs help to walk around at night.

When Alisha Bacoccini was born, her mother, Eve Skidmore, could tell right away that something was wrong. Alisha seemed to focus only on bright light, like a window or lamp, Skidmore says. She thought her daughter might just need glasses, but the ophthalmologist said the little girl was going blind and nothing could be done. She was diagnosed with a progressive eye disease at 11 months, and a genetic test eventually identified the disease as LCA. As a child Alisha could still see well enough to play soccer with a white ball on green grass. "She was extremely fast," says Skidmore, which made up for not seeing the ball in the air. Around eighth grade, Alisha lost even that limited vision.

Today she can read text on a bright computer screen but not in a book. She works as a massage therapist. If she could see better, her dream job would be to work as a forensic pathologist—she devours Patricia Cornwell novels on tape. Skidmore wishes her daughter could regain enough sight "to see the stars in the sky and a rainbow, because she's never seen that."

Bacoccini says she realizes that her sight may not improve in the gene-therapy study, and could even get worse. She volunteered to take part so she could "help to figure out how to fix blindness," she says.

Three months after Maguire injected Bacoccini's eyes with the viruses carrying the retinal gene, her eyes were ten times more sensitive to light and her peripheral vision had improved, but she could not read an eye chart any better than before. Bennett says there are several reasons the treatment may not be working well for her—for example, the neural circuits between Bacoccini's eye and brain may no longer function properly.

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