Gene Therapy and Leber Congenital Amaurosis: Update from the National Eye Institute

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The following update addressing the role of gene therapy in the treatment of Leber congenital amaurosis (LCA), an inherited and progressive eye disease, is adapted, with permission, from a National Eye Institute news brief entitled New Findings Suggest Need for Combined Strategy in Treatment of Rare Form of Blindness. The mission of the National Eye Institute is to “conduct and support research, training, health information dissemination, and other programs with respect to blinding eye diseases, visual disorders, mechanisms of visual function, preservation of sight, and the special health problems and requirements of the blind.”

Gene Therapy and Leber Congenital Amaurosis (LCA): Some Background

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 Leber congenital amaurosis (LCA), an inherited form of progressive blindness, using gene therapy.

In 2013, however, the team 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. These findings have been published in the January 22, 2013 early online edition of Proceedings of the National Academy of Sciences in Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement.

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.

The Gene Therapy Process

“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 Study Explained

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 of the study. “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.”

Why Does Retinal Degeneration Continue?

The scientists are unsure why retinal degeneration continues despite treatment, but speculate that the lack of a normally-functioning RPE65 gene promotes cellular stress and the subsequent onset of programmed cell death, a process 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.

Other Gene Therapy Trials for LCA

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.

(Note: In Phase I clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe and effective dosage range, and identify possible side effects.)

The Future of Gene Therapy for LCA

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.”

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 at Phase I Trial of Gene Vector to Patients with Retinal Disease Due to RPE65 Mutations (LCA).