A Gene to Cure Blindness

It

took 15 years to get the right gene, to neutralize a virus that could carry it, and to prove — first in test tubes and then in live animals — that the procedure was safe enough for humans. Finally a young man named Robert Johnson got the first shot. A team of U.K. doctors announced earlier this month, that they put a needle through Johnson's eye, into his retina, to replace the faulty gene that had been blinding him for years.

That injection made Johnson the first person ever to undergo gene therapy for an eye condition, although it may take months to determine if the procedure worked. A second patient received the same treatment shortly after Johnson, and 10 more will soon follow suit — names and dates all undisclosed — as part of a trial led by Robin Ali, a professor of human molecular genetics at University College London, and conducted at Moorfields Eye Hospital in London.

All 12 patients have a faulty gene that gives them a form of Leber's Congenital Amaurocis, a major cause of congenital blindness. Born with limited sight, the patients are expected to become totally blind as they grow older. They have enough photoreceptor cells, but the cells don't work because one of the genes is a dud. Now Ali is firing functional versions of the faulty gene back into the photoreceptor cells, and the one-time procedure could permanently cure the blindness. Johnson's condition — a faulty RPE65 gene — is incredibly rare. But Ali says the procedure, if it works, could be used to treat any one of about 100 inherited single-gene sight disorders that, together, affect 1 in 2,000 or 3,000 people.

Ali's trial at Moorfields is not a conceptual breakthrough for the young science of gene therapy — there have been other trials on procedures in other organs — but, as a milestone, it's a good marker of where the field stands today. At its most basic, gene therapy is anything that introduces new genetic material to help fight or prevent a disorder. Treatment options are still in the experimental stages, and are not free of philosophical critics. But gene therapy has also been heralded as a potential cure for all kinds of genetic diseases (think cystic fibrosis or sickle-cell anemia) and even for cancer — with promising lab results to back up the hype. For that reason, gene therapy is a hive of research activity. Ali is joined by many others, at the universities of Pennsylvania, of Florida, and of Iowa, for example, who have spent years working to develop gene therapy for the eyes. Then there are the countless researchers working on other gene-therapy problems, either at the theoretical level or in other organs, or both.

The field's main challenge today is getting the best of that research ready, through trials like the one at Moorfields, so that patients to reap the benefits. "Moving something from the laboratory into the clinic, the difficulty of doing that is enormous," says Ali in London. "It's very exciting that we've managed to get this far."

And it's taken ingenuity. In patients like Robert Johnson, Ali delivers the functional gene using a virus that's been modified so it won't attack the eye or reproduce. The two trial subjects so far have not had severe immune responses to the new matter in their eyes — always a danger. Scientists are especially hopeful because the procedure worked so well in its animal trials. Scanning the eyes of dogs that underwent the procedure, researchers could see how the photoreceptor cells had changed. More important, the previously blind dogs could see well enough to navigate through a maze.

Ali says he expects it will be at least a year — and probably longer —before any results of his trial are published. It can take months for the new genes to take effect. He is, however, "optimistic." He's not alone. "I don't have any doubt this is going to be a real home run. The people in this trial, they're going to be out playing Frisbee, seeing their girlfriends' and boyfriends' faces for the first time," says Jeffrey Boatright, a self-described "second-generation" gene-therapy researcher at Emory University in Atlanta. The U.S. National Eye Institute issued a statement to say the procedure "opens the door to treatment of a whole repertoire of genetic eye diseases." There's hope that, one day, gene therapy might be developed to tackle more complex sight disorders with a genetic component, like age-related macular degeneration.

Boatright and his colleagues are working on a technique that would let ophthalmologists fix genes that not just fail to express themselves, like Robert Johnson's, but that have mutated in a way that they express themselves abnormally, a trickier proposition because doctors need to add something and suppress something else at the same time. (Boatright and co. would inject short DNA strands that, where they bound with the patient's DNA at the point of the fault, would alert the body's existing repair mechanisms to the problem). The future looks bright indeed.