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Retinal disease gene therapy: benefits for Leber congenital amaurosis peak after one to three years, then diminish

Gene therapy for Leber congenital amaurosis ( LCA ), an inherited disorder that causes vision loss starting in childhood, improved patients’ eyesight and the sensitivity of the retina within weeks of treatment. Both of these benefits, however, peaked one to three years after treatment and then diminished, according to results from an ongoing clinical trial funded by the National Eye Institute ( NEI ), part of the National Institutes of Health.

The results published in the New England Journal of Medicine ( NEJM ) focus on a subset of trial participants who routinely underwent extensive tests of their vision and imaging of the retina from baseline up to six years after treatment. These in-depth examinations revealed that the areas of treated retina rapidly gained visual sensitivity, expanded and then contracted.

Leber congenital amaurosis is an inherited disorder that causes vision loss in childhood. It primarily affects the functioning of the retina, the light-sensitive tissue at the back of the eye.
About 10% of people with Leber congenital amaurosis carry a mutated form of the gene RPE65, which makes a key protein found in the retinal pigment epithelium, a layer of cells that nourish the light sensors or photoreceptor cells of the retina. The RPE65 protein is critical for vision. In the retina, millions of photoreceptors detect light and convert it into electrical signals that are ultimately sent to the brain. Photoreceptors rely on the RPE65-driven visual cycle to recharge their light sensitivity. They also need RPE65 for their long-term survival. In Leber congenital amaurosis, the cells eventually die, muting eye-to-brain communication.

Jacobson along with Artur V. Cideciyan, at University of Pennsylvania, and William W. Hauswirth, at University of Florida, Gainesville, began the trial in 2007. Fifteen people with Leber congenital amaurosis received retinal injections of a harmless virus engineered to carry healthy RPE65 genes.
This gene therapy relies on viral vectors as a means to deliver instructions for making the desired protein. In this case, the virus was designed to produce healthy RPE65.
Hauswirth led the group that designed and produced the virus-gene material for testing in patients.

Within days of the injections, some patients reported increases in their ability to see dim lights they had never seen before. In addition to the rapid onset of greater light sensitivity, the researchers discovered changes to another component of vision that occurred slowly. Four of the 15 patients started relying on an area of the retina near the gene therapy injection site for seeing letters. Normally, the fovea with its high density of photoreceptors is responsible for seeing fine details.

For some patients, preferential use of the treated area for seeing letters came about spontaneously about a year after the gene therapy and remained functional for up to six years.

For the current study, Jacobson’s team also examined the relationship between structure and function in the retina. Importantly, these results showed that photoreceptors continued to die at the same rate as they do in the natural course of the disease, regardless of treatment. The researchers concluded that gene therapy with RPE65 boosted the visual cycle, but did not delay photoreceptor cell death. Hence, the short-term gains in visual function. ( Xagena )

Source: National Institutes of Health, 2015