February 2010




Eyeing gene therapy

by Maxine Lipner Senior EyeWorld Contributing Editor


New treatment enables previously “blind” children with Leber’s congenital amaurosis to be mainstreamed

A new gene therapy regimen offers hope to patients with a form of Leber’s congenital amaurosis, including some children who were able to subsequently attend sighted classes, according to Katherine A. High, M.D., professor of pediatrics, University of Pennsylvania School of Medicine, Philadelphia. Recent results published in the Nov. 7, 2009, issue of Lancet showed visual improvement in all patients using both subjective and objective measures.

In the study involving 12 subjects ages 8 to 44, all were given one subretinal injection of a vector of adeno-associated virus (AAV) containing an intact copy of a gene that was defective in these Leber’s congenital amaurosis patients. “The idea is to deliver it into the subretinal space,” Dr. High said. “From that space it contacts the retinal pigment epithelial cells, which are the ones that have a defective copy of the gene, and it goes into the cells and starts making the missing protein.” By putting the gene back in the eye, the visual cycle is reconstituted and patients once again develop the ability to respond to light.

Targeting younger patients

Going into the trial, investigators were most optimistic about how younger individuals would respond to the gene therapy. “All the preclinical data suggested that the best response would be in younger people,” Dr. High said. “The data in a mouse model and a dog model had shown that if we can give the gene relatively early in the life of the animal we could rescue vision, but if we go in too late there’s nothing left to rescue.”

With this in mind, investigators originally sought to concentrate on patients ranging in age from 8 to 27. “We thought those ages corresponded to the window where things worked in the animal model,” Dr. High said. “But we found that in the first few subjects, even people up to 27 years of age were having a response so we decided to include older subjects in the trial.” The oldest patient included was 44 years old. “She, too, had a response,” Dr. High said. As a result, no upper age limit for the therapy has been defined as of yet.

What did become clear was that in humans, as in other species, the best response was in the youngest patients. “There were four children that were in the range of 8 to 11 years of age and they had startling best responses compared to the adults,” Dr. High said. While all patients developed improvements in measures of retinal visual function, such as visual acuity or visual field testing, sensitivity to light and after dark adaptometry, it was in mobility that the children really stood out. “Everyone demonstrated some combination of improvement,” Dr. High said. “The thing that was different about the children was that in a mobility test where they were asked to traverse an obstacle course following black arrows on the floor, the children developed the ability to navigate the obstacle course especially with the treated eye.” If this eye was patched, they were unable to complete the task. This gain in mobility for the children also corresponded with impressive gains in areas such as pupillary light response. Following the treatment, one 8-year-old subject demonstrated the same level of light sensitivity as a normal subject the same age. All of the children improved enough to be mainstreamed. “They were able to move out of Braille classrooms and into sighted classrooms,” Dr. High said.

Rapid improvement

Following the subretinal injection, improvement is rapid. “People start to notice something after about two weeks,” Dr. High said. “The first subject was treated about two years ago and seemed to exhibit gradual improvement through that course.” However, the AAV vectors themselves tend to peak rapidly. “They reach a plateau of expression at about eight weeks after injection,” Dr. High said. She theorizes that the fact that people continue to improve long after this may have to do with central nervous system plasticity. “The concept is that you could be reassigning neurons to process visual input,” she said. “Of course, you would expect that to happen most effectively in a child.”

So far, the effect of the gene therapy appears to be long-lasting. “In dogs it has lasted for 10 years and counting and in humans for two years and counting,” Dr. High said. “My feeling was that if we were going to see a problem that was going to limit the duration of expression, it would happen within a few weeks of injection.” Because that did not occur, Dr. High remains cautiously optimistic about how long the effect might last. “The fact that the effect is still present two years later is very good, but only time will tell how long it’s going to last and whether humans will do as well as large animals,” she said.

Going forward, there is hope that the approach may also work for other retinal degenerative disorders. “There are trials in the planning stages in terms of inherited diseases for Leber’s heretic optic neuropathy and also for x-linked retinal skesis,” Dr. High said. “There’s also a proposal to start a trial within the next year for macular degeneration using the same kind of vector delivered to the eye.”

Editors’ note: Dr. High has no financial interests related to her comments.

Contact information

High: 215-590-4521, high@email.chop.edu

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