The small, windowless space at the Children's Hospital of Philadelphia looks like any eye doctor's examining room, with an adjustable chair and half a dozen machines for testing vision. The 20-year-old patient, however, has not come all the way from Albuquerque to get new glasses. Alisha Bacoccini, who has short, blond-streaked hair and green eyes, was born with a disorder caused by a malfunctioning gene in her retina cells that has been diminishing her sight since birth. Now she sees only pale and blurry shapes. "If I look at you I can't see eye color or acne or your eyebrows, but I can see that someone's there," she says. Her seeing eye dog, Tundra, a black Labrador retriever, sits at her feet.
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A month earlier, in an experimental treatment, researchers injected Bacoccini's right eye—the worse one—with billions of working copies of the retinal cell gene. Now they'll find out if the treatment has worked.
Jean Bennett, a physician and molecular geneticist, has Bacoccini rest her forehead against a small white machine that flashes light into one eye, then the other. This pupillometer will indicate how well Bacoccini's eyes respond to light. "OK, one, two, three, open," Bennett says, and repeats the procedure 16 times. On a computer screen in the darkened room, Bacoccini's pupils are two giant black circles that contract ever so slightly with each pulse of light. Another researcher escorts Bacoccini to the next testing apparatus. Half an hour later, Bennett says: "I just looked at your pupillometry results. Good improvement."
"That's good," Bacoccini says, though she sounds unsure. Since a few days after the injection, she has indeed seen more light out of that eye, she says, but things seem blurrier. When she tries to read a giant eye chart with her right eye, she does no better than before—she can pick out only a few two-inch-high letters from 16 inches away. Then again, her eye is still red from the surgery. Bennett's husband, Albert Maguire, is the retinal surgeon who operated on Bacoccini. He peers into her eye and says the surface hasn't yet healed, adding: "Hopefully, that's all it is."
The prospect of using gene therapy to treat diseases—particularly inherited diseases that involve one errant gene, such as sickle cell anemia and cystic fibrosis—has tantalized scientists for decades. If there were some way to give a patient a good version of an implicated gene, the thinking goes, it might repair or prevent damage caused by the inherited bad one. This seemingly simple idea has turned out to be unexpectedly complex in practice. There have been hundreds of human gene-therapy trials for many diseases, from hemophilia to cancer, in the past 18 years. But nearly all failed because of the difficulties of getting a working gene into cells without also causing harmful side effects.
Until last year, gene therapy had worked unequivocally against only one disease, the rare affliction called severe combined immuno-deficiency (SCID), which is caused by a flaw in any of a number of genes needed to produce white blood cells. The disease leaves the immune system unable to fight infections and usually leads to death in childhood. It is also called "bubble boy" disease, after one famous patient, David Vetter, who lived to age 12 in a sterile plastic bubble. Since the mid-1990s, European researchers have cured about 30 kids with SCID by inserting the appropriate functioning gene into their bone marrow. But even this success has been mixed with tragedy: five of the children developed leukemia and one has died. In those patients, who had a particular variant of the disease, the therapeutic gene accidentally turned on a cancer-causing gene after merging with the patients' DNA. Researchers are now testing ways to make gene therapy for SCID safer.
U.S. gene-therapy research was set back substantially after 18-year-old Jesse Gelsinger, who suffered from an inherited liver disease, died of multiple organ failure in 1999 while participating in a gene-therapy experiment at the University of Pennsylvania. News of the death prompted an uproar in the scientific community and hearings in Congress, with the teenager's father, Paul Gelsinger, and others accusing the Penn researchers of being too hasty to test the treatment in people. According to the Food and Drug Administration, the researchers had not sufficiently warned Gelsinger and his family of the experiment's risks. The lead researcher had also failed to disclose that he had a financial stake in a company that stood to gain if the treatment succeeded. "Those were the terrible days. The field bottomed out," says Leon Rosenberg, a Princeton University human geneticist, who performed early lab studies on the liver disease that Gelsinger had. "The integrity of science was damaged tremendously."
Bennett and Maguire joined the Penn medical school faculty in 1992. One of their colleagues is James Wilson, who oversaw the study in which Gelsinger died. Wilson was subsequently barred by the FDA from conducting human experiments. But Bennett and Maguire were not involved in that study. Their experimental gene-therapy trial began in 2007 after years of review by federal regulators, the Children's Hospital and Penn committees set up to address ethical and safety concerns raised by Gelsinger's death.
This past May, their team and a separate British group reported the first hopeful gene-therapy news in years: the technique could treat blindness. The patients in the study had a disease called Leber congenital amaurosis (LCA). The three patients whom Bennett and Maguire treated were able to read several more lines of an eye chart than they could before. One 26-year-old man even regained enough sight to walk through a maze. "I couldn't believe it," Bennett says. She made him walk the maze over again.
The study was small, and the patients are still legally blind, but their modest improvement and the apparent safety of the therapy have aroused the hopes of patients and researchers around the world. Now Bennett and Maguire are extending the research to more patients with LCA, including Bacoccini, to test whether patients can safely receive higher doses of the therapeutic gene.