September 2008




Refurbishing sight to patients with rare congenital blindness

by Maxine Lipner Senior EyeWorld Contributing Editor



Investigators have used gene restoration to safely improve blinded patients’ vision

New hope in the form of gene therapy has emerged for young adults blinded by Leber congenital amaurosis. Results published in the May 2008 issue of the New England Journal of Medicine indicate patients improved from being able to only detect hand motions to reading lines on the eye chart, according to Jean Bennett, M.D., professor of ophthalmology, University of Pennsylvania, Philadelphia, and senior investigator, F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania.

“This is a form of Leber’s congenital amaurosis marked by a defect in the RPE 65 gene,” Dr. Bennett said. “RPE 65 is an enzyme that plays a role in recharging the vitamin A compound that’s necessary for the photoreceptors to be able to actually start the whole process of vision.” Because this vitamin A compound is missing, the patients lose their vision. Investigators hoped that gene therapy could correct the problem. “The strategy is really quite simple in that we’re delivering that enzyme to correct the biochemical pathway and to open the circuit again,” Dr. Bennett said.

Three-tier study

Investigators here launched a dose escalation study to determine the safety and efficacy of the approach. To this point they are currently reporting on the first three patients, all of whom received the lowest dose of the gene therapy. “We used a subretinal injection of a recombinant virus called Adeno-associated virus, to deliver the normal DNA encoding RPE 65,” Dr. Bennett said. “It delivers that DNA to the retinal pigment epithelium cells.” Treatment here called for a single injection to be placed in the more severely affected eye. “It’s only a single injection because we believe that there is a potential that this will really lead to long-term vision restoration—particularly since dogs that we have followed since July 2000 after one injection are still seeing well.”

Gaining visual ground

The three initial patients here, who were all severely visually impaired, responded well to the low-dose therapy. Prior to the treatment, two were only capable of seeing hand motions and one could read the first line on the eye chart at a very close distance. None could see well in dim light, according to Dr. Bennett. Following the therapy this changed. “What they first noticed starting about two weeks after the injection was that everything seemed brighter in their treated eye,” she said. “It was confusing to them at first because the other retina was still really dim.” Then they began to see other improvements as well. “With time they realized that they could actually make out objects that they couldn’t see before,” Dr. Bennett said. “For example they found they could see furniture, signs, numbers on their cell phone, and things like that.”

These subject reports of improvement corresponded with objective testing that was done as well. “Within a month after injection all of the patients could read at least four lines on an eye chart,” Dr. Bennett said. “Also their pupil responses were restored in their injected eye but not in the control eye.” The patients also reported that they could navigate better. In one case this was substantiated by the testing as well.

While the biggest visual gains were attained during the first six weeks, patients did continue to show some improvement after that. “We were surprised that one of the subjects who has been out the second longest, seven months now, continues to improve in terms of visual acuity and the eye chart,” Dr. Bennett said. The patient who has been followed the longest—nine months—also continues to show slow improvement. Investigators are unsure whether this late improvement is a result of the gene transfer itself or is due to neuroadaptation, with the brain becoming more attuned to the retina’s signals. There were no severe adverse events. The most significant complication involved a macular hole, which was found at the two week checkup. “There was an epi-retinal membrane before injection and we hypothesize that during the injection that retracted and led to this hole,” Dr. Bennett said. In this case it did not impair the patient’s vision. Investigators here, however, have taken steps to minimize this from occurring in the future.

Currently, the investigators have moved on to patients receiving the gene therapy at the medium dosage level. “We expect that there will potentially be even better improvements in the vision of the patients treated with the higher dose, but it also has the potential of increasing toxicity,” Dr. Bennett said. So far, the first of the two patients on the intermediate dose has done very well. The second is due to undergo initial monitoring.

Overall, Dr. Bennett sees the results as boding well for other genetic eye diseases as well. “I think that it’s very exciting that now we really do have evidence that this sort of approach can be effective for improving vision in a severe blinding condition,” she said. “This has brought a lot of hope to people who have different varieties of inherited retinal diseases.”

However, realistically speaking, with 140 different genes implicated in retinal degeneration, it likely will be too costly to bring these all to clinic. Instead Dr. Bennett thinks another approach might be needed. “The one hope I have is that it will be possible to develop a general strategy to keep the cells alive and happier for longer by developing a gene which does that, for example a neurotrophic factor,” she said. “That sort of strategy could be used for any variety of retinal degeneration and I think that’s more realistic.”

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

Contact information
Bennett: 215-898-0915,

Refurbishing sight to patients with rare congenital blindness Refurbishing sight to patients with rare congenital blindness
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