Gene Therapy Improves Vision but does not Slow Vision Loss

February 4, 2013 - Retinal degenerative diseases, such as retinitis pigmentosa and Leber congenital amaurosis, are usually caused by mutations in a single gene. In recent years, scientists have developed gene-replacement therapies as a way of replacing the functions that were lost because of these mutations (see our gene therapies fact sheet for details). Each treatment is specific to one specific genetic type of eye disease.

In the last five years, these treatments have begun to be evaluated in human trials. The initial results of these trials showed that gene therapies can improve vision. The first gene therapy to be tested, for people with Leber congenital amaurosis due to a mutation in RPE65, has now been used in more than 15 people. All of them experienced some improvements in vision.

Scientists can now study the longer-term effects of gene therapy, since it has been several years since the people in the first RPE65 trials received treatment. While the treatment appears to have produced a lasting, long-term benefit in improved function of visual cells, newly published studies show that it does not make the cells in the treated area live longer.

Loss of retinal cells causes loss of vision and thinning of the retina. In the treated RPE65 patients, treated parts of the retina lost cells at the same rate as untreated parts of the retina.

"When compared, the photoreceptor cell layers of treated and untreated eyes became thinner at a similar pace," says Dr. Samuel Jacobson, a professor at the University of Pennsylvania’s Scheie Eye Institute.

“Gene therapy improved vision but did not slow or halt the progression of cell loss,” noted his colleague, Dr. Artur Cideciyan, lead author of the study.

These results were unexpected, but the scientists report that they have now observed similar results in the dogs that were first treated with the same LCA gene therapy. The scientists are unsure why cell death continues, suggesting that perhaps abnormalities in surrounding cells continue to stress the treated cells, or perhaps some cells reach a point of no return, so that once slated for destruction they are not saved even though their functioning improves.

“These findings illustrates how complicated the effects of disease-causing gene mutations are,” says Dr. Bill Stell, Expert Scientific Advisor to the Foundation Fighting Blindness. “Much more basic research will be required, to understand how visual cells in the retina respond to the loss-of-function mutations in LCA-RPE65 and to gene replacement therapy.”

One possible solution is to use therapies in combination. Many research teams have been developing therapies that halt cell death. (See our anti-apoptosis therapies fact sheet for details). Perhaps by combining these therapies with gene therapies, the newly functioning cells can be protected.

“Slowing cell loss in different retinal degenerations has been a major research direction long before the current gene therapy trials”, says Dr. Jacobson. “Now, the two directions must converge to ensure the longevity of the beneficial visual effects in this form of LCA.”

This research was published in the Proceedings of the National Academy of Sciences.


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