By Rick Weiss
Washington Post Staff Writer
Monday, April 28, 2008
Three young adults barely able to see because of a congenital and progressive form of blindness have regained modest amounts of vision after getting genetically engineered viruses injected into their eyes, the leaders of two independent studies reported yesterday.
The results were something short of miraculous. Three other patients showed no increase in visual acuity, and the three who improved are still legally blind.
But to get any improvement at all during such an early phase of the research suggests that the approach has promise for people with gene-based forms of blindness, researchers said. The work could also provide a boost for the field of gene therapy, which for 15 years has tried and mostly failed to treat diseases by giving people new genes -- and in a few high-profile cases has sickened or even killed them.
"We're learning things as we go along," said Jean Bennett of the University of Pennsylvania, who with Albert M. Maguire led one of the two studies. "We were not really going for a cure. But we do view it as a success in that their vision has improved. I'd call it a dramatic response."
Others took a more conservative view, noting that some of the key measures of improvement were subjective and could not be conclusively linked to the therapy. In an editorial to appear in the New England Journal of Medicine along with the study results, Joan W. Miller of the Massachusetts Eye and Ear Infirmary called the results "suggestive of efficacy."
Still, videos of some of the experimental subjects trying to navigate through a dimly lit obstacle course show notable improvement in the weeks and months after the injections. Scientists said they are hopeful that the treatment will prove even more beneficial in younger patients, whose retinas have only begun to degenerate.
"If we can get any benefits in people with such advanced disease, then when we start to treat children, and when we treat a greater part of the retina and give a higher dose, the expectation is we can get even better results," said Robin R. Ali of University College London, who led the other study.
Both teams are moving ahead with tests in younger patients and at higher doses.
The experiments involve patients with Leber's congenital amaurosis, a rare disease caused by a defect in a single gene that is crucial to the retina's ability to convert light into signals to the brain. Affected children have impaired vision from birth and are typically blind by age 30.
The British and Pennsylvania teams took somewhat different approaches. Each involved what are known as adeno-associated viruses, popular among gene-therapy researchers because of their ability to deliver new genes to cells.
In this case, the teams used genetic engineering techniques to load the viruses with healthy versions of the rpe65 gene, the gene that is faulty in people with Leber's. Then they injected tens of billions of the viruses into the tiny space behind the retina.
They treated just one eye of each patient, in part so as not to put both eyes at risk of side effects but also to allow for comparisons of visual acuity after the treatment.
The Pennsylvania team, whose patients were ages 19 to 26, reported the more impressive results. All three scored better on visual acuity tests, showing improvements equivalent to being able to read three lines lower on a standard eye chart, after initially not being able to make out the very largest letter. The treated eyes of all three patients also became about three times more responsive to light as measured by how much the pupils contracted.
One patient suffered retinal damage, apparently as a side effect, though team members said they think they know how to avoid that in the future.
One patient also experienced a small improvement in an untreated eye. That unexplained effect in part highlights the limitations of acuity tests, which are subject to factors such as general health, mood and the placebo effect.
Indeed, experts said, there is no way short of an autopsy to know whether the injected genes integrated into the retinal cells and are functioning.
The British study, using a somewhat different viral vehicle made by Targeted Genetics of Seattle, treated three patients, ages 17 to 23. Only one-third of the retina of each treated eye was injected, out of an abundance of caution. One patient had significant improvement in light sensitivity, but none had better acuity.
In both studies, some patients were for the first time able to get through a cluttered, dimly lit room unaided, according to the reports. They will be published in May but were released yesterday to coincide with a presentation at a medical conference.
"Before treatment, you can see he bumps into the walls and he's disoriented and has to be pointed in the right direction. He clearly just feels his way around," Ali said of one patient, who was videotaped before and after. "Six months after surgery, he could walk through without bumping into anything and take the same length of time that a normal person could."
That patient, Steven Howarth, said in a statement released by Targeted Genetics that he is pleased.
"Now, my sight when it's getting dark or it's badly lit is definitely better. It's a small change -- but it makes a big difference to me," Howarth, 18, said.
Paul A. Sieving, director of the National Eye Institute, which led the research that identified the rpe65 gene but was not involved in the latest research, said Howarth's anecdote jibes with his observation that even modest improvements in vision can make for big gains in the quality of one's life.
"From the numbers, you can't imagine there's any real improvement," Sieving said. "But if I give you just a little vision, someone on the street can't even tell you have an impairment."
About 450 genes have been implicated in eye diseases, Sieving said, suggesting that the approach could have potential for many.
Arthur W. Nienhuis, president of the American Society of Gene Therapy and a faculty member at St. Jude Children's Research Hospital in Memphis, called the results "highly encouraging."
"I think the field is really beginning to turn the corner," Nienhuis said.