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

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)
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Rosenberg says he is "delighted" for Bennett—who was a postdoctoral researcher in his lab in 1987—and the field. "I'm optimistic about gene therapy again and I haven't been for a while," he says. "Hopefully before the end of this decade there will be two or three other examples."

For both Bennett, 54, and Maguire, 48, science would appear to be in their genes. Bennett's mother, Frances, taught high-school literature and her father, William, was a popular physics professor at Yale who had co-invented the gas las­er in 1960 while working at Bell Labs in New Jersey. Bennett remembers being 6 years old and seeing her father race back to the lab after dinner to work until dawn; the device later led to compact disc players and supermarket price scanners.

She was more interested in biology than physics. "I loved creatures," she says, and spent many happy hours looking through her father's microscope at swamp water and leaves. After college at Yale, she went to the University of California at Berkeley to earn a PhD in developmental biology, using sea urchins, but she was drawn instead to then new research on inserting specific, foreign genes into mice and other animals—a forerunner of gene therapy. She spent several months in 1981 and 1983 at the National Institutes of Health in Bethesda, Maryland, in a lab where scientists were planning some of the first gene-therapy trials. "It was a glimmer that it was going to happen that got me excited. I wanted to be there as the field developed," Bennett recalls. To get the clinical background she needed, she went to Harvard Medical School, where she met her future husband in a first-year anatomy class.

Maguire also came from a family of scientists. His father, Henry, was a dermatologist and is now a cancer vaccine researcher at Penn, and his mother, Elise, worked there as a research assistant. Henry had cataracts and later retinal detachment. When Maguire was in high school, he administered his father's eyedrops—his earliest foray into ophthalmology treatment. In medical school, Maguire worked in a lab that studied retinal diseases caused by inherited gene defects. He remembers asking Bennett at the time if the bad genes could be fixed. "That makes sense," she told him. "Let's do it."

The eye is especially well suited to gene therapy. The cells into which a new gene must be inserted are limited to a small area; the retina contains only a few million cells. What's more, unlike most cells, retinal cells don't divide after a person is 3 months old, so researchers don't have to get the new gene into future generations of cells. That means they don't have to stitch the new gene into the cells' existing DNA, which is replicated when a cell divides. Keeping the therapeutic gene separate from the patient's DNA is safer; in the SCID patients who developed leukemia, the introduced gene was incorporated near a cancer-causing gene and accidentally switched it on. The eye is also immunoprivileged, meaning the immune system tends to ignore foreign material introduced there. A runaway immune response has been a problem in some gene-therapy trials and is what killed Jesse Gelsinger. "We're very lucky with our choice of target organ," Maguire says.

While Maguire trained to become a retinal surgeon, Bennett continued to specialize in research rather than clinical work, following her husband around the country for his internship, residency and fellowship. Complicating matters, they were traveling with toddlers. In their last year of medical school, the newlyweds had their first baby—"our senior project," they call it. Two more children soon followed.

In 1989, during one of Maguire's last training stops, in Royal Oaks, Michigan, Bennett set up makeshift labs in the building next door to the hospital and in the basement of their home. They conducted what they think was the first gene-therapy experiment involving the retina. Using mice and rabbits, they injected a gene for an enzyme found in bacteria. They used a dye to reveal whether the eye cells had built the enzyme, and the experiment succeeded: the animals' retinas turned blue for about two weeks.

At Penn, they published one of the first two papers showing that a virus endowed with a foreign gene could shuttle it into eye tissue, in this case in mice. (This strategy, common in gene-therapy experiments, essentially co-opts the virus' capacity to replicate by injecting its own genetic material into cells.) Bennett and Maguire later inserted therapeutic genes into the eyes of some Irish setters with inherited blindness. But Bennett thought the improvement in the dogs wasn't compelling enough to warrant a human trial. What they needed was a simple, slowly progressing form of blindness that was related to a disease that afflicts people. In 1998, they learned of a breed of briard dog in Sweden with an eye disease that, by a fluke, happened to be caused by one of the genetic mutations found in some patients with LCA.

About 3,000 people in the United States suffer from LCA, which encompasses several different blindness disorders that begin in childhood and are caused by mutations in any of several genes, one of which is called RPE65. It contains the instructions for an enzyme crucial to the retina's light-sensing cells, the rods and cones; the enzyme converts vitamin A into a form that the rods and cones use to make a necessary pigment, rhodopsin. In people who inherit a bad copy of the RPE65 gene from each parent, the rods and cones, deprived of rhodopsin, malfunction and eventually die.

Bennett, Maguire and co-workers used a virus called adeno-associated virus to insert a good copy of the RPE65 gene into three young briards. The AAV virus' two genes had been replaced with the RPE65 gene plus a string of DNA that switches the gene on. The dogs regained enough vision to navigate a maze. "It was fantastically exciting," Bennett says. One dog, Lancelot, became a kind of poster dog for gene therapy, shaking paws with people at press conferences and fundraisers.


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