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New Findings Suggest Need for Combined Strategy in Treatment of Rare Form of Blindness

January 25, 2013

In 2008, a team of scientists funded by the National Eye Institute (NEI), a part of the National Institutes of Health, reported major progress in the treatment of an inherited form of progressive blindness using gene therapy. The team now reports that although treatment improved eyesight, cells in the eye crucial for vision continued to diminish in number. This new finding suggests a need for a combination therapy that restores vision and protects the eye’s cells. The findings are published in the January 21 early online issue of Proceedings of the National Academy of Sciences.

The disease, known as Leber congenital amaurosis (LCA), is caused by mutations in a gene involved in vitamin A metabolism called RPE65. The disease negatively affects a person’s eyesight in two ways. First, the inability to process vitamin A reduces the ability of specialized nerve cells in the retina, called photoreceptors, to send visual information to the brain. The retina is the layer of tissue in the back of the eye. Second, the disease causes early death of some photoreceptor cells. As a result of these two disease mechanisms, people with LCA are born with limited vision that diminishes over many years as photoreceptor cells are progressively lost.

“Many scientists had assumed, and we had all hoped, that delivering the RPE65 gene to the retina would not only improve vision but would also arrest photoreceptor cell degeneration,” said Artur V. Cideciyan, Ph.D., a professor of ophthalmology at the University of Pennsylvania Scheie Eye Institute and lead author of the study. “This study shows that degeneration continues despite gene augmentation.”

The gene therapy procedure developed by the team works by introducing copies of normal RPE65 genes into patients’ retinal cells through the use of an adeno-associated virus (AAV) vector. A total of 15 study participants received one or more injections of genetically modified RPE65-AAV vector into select areas of the retina of one eye. The other eye served as a control. Within days after treatment, vision in the participants’ treated eye significantly improved. In 2011, the team published a report of a three-year follow-up study that showed visual gains were retained.

The present study aimed to determine if the gene therapy stopped or slowed photoreceptor degeneration. Dr. Cideciyan and colleagues estimated the rate of thinning of the photoreceptor layer in the retinas of treated and untreated eyes over a period lasting up to 6.5 years using a noninvasive technique called optical coherence tomography (OCT). OCT is similar to ultrasound but uses light waves instead of sound waves to image internal tissues. Using OCT, the scientists were able to accurately measure the thickness of the photoreceptor cell layer in treated and untreated eyes as well as untreated areas within treated eyes. The scientists also measured the rate of thinning in an additional eight participants with LCA who were not treated with gene therapy.

“Based on our latest study, photoreceptor cell loss in eyes treated with RPE65 gene therapy continues at a rate no different than the expected natural progression of the disease,” said Samuel G. Jacobson, M.D., Ph.D., professor of ophthalmology also at the University of Pennsylvania Scheie Eye Institute, and a co-author on the report. “When compared, the photoreceptor cell layers of treated and untreated eyes became thinner at a similar pace, decreasing at about 9.6 percent a year.”

The scientists are unsure why retinal degeneration continues despite treatment but speculate that the lack of a normal-functioning RPE65 gene promotes cellular stress and the subsequent onset of programmed cell death, a process otherwise known as apoptosis. Once initiated, the cell death cannot be reversed simply by restoring RPE65 gene function. The report also detailed research in animals, which shows that RPE65 gene therapy also does not halt photoreceptor cell degeneration if administered at a comparable time in the disease to that in humans.

Three other gene therapy trials have successfully improved vision in people with LCA using RPE65 gene therapy. Drs. Cideciyan, Jacobson, and their team are the first to document the continuation of degeneration after treatment. All of the LCA trials are phase 1, meaning they were designed to test safety. To date, none of the trials has reported the occurrence of a serious side effect from use of the AAV gene therapy vector.

The scientists envision a combined therapeutic approach that both restores gene function and protects cells. The latter, they say, could possibly be achieved through the administration of neuroprotective agents such as growth factors or antioxidants in concert with RPE65 gene therapy.

“These early trials demonstrate that gene therapy is safe and capable of achieving remarkable and lasting improvements in vision,” said Dr. Cideciyan. “To build upon these successes requires re-evaluation of the molecular and cellular underpinnings of the degenerative process that occurs with LCA.”

Animal studies described in the report were conducted by Gustavo D. Aguirre, V.M.D., Ph.D., and William A. Beltran, D.V.M., Ph.D., of the University of Pennsylvania School of Veterinary Medicine. The RPE65 gene therapy vector was developed by William W. Hauswirth, Ph.D., University of Florida College of Medicine.

This research was supported by extramural funding at the NEI under grant numbers U10 EY017280, R01 EY006855, R01 EY017549, R01 EY019304, R01 EY022012. Information about the LCA clinical trial can be found by searching for clinical trial number NCT 00481546 at