Posted on March 12, 2001 at 8:53 a.m.

BIRMINGHAM, AL — In a groundbreaking study, researchers have found a way to restore vision in blind mice who suffer from a rare retinal degenerative disease known as Leber congenital amaurosis (LCA).

Although the disease is rare, the finding represents hope that it may be possible to develop sight-restoring treatments for other forms of retinal degeneration before retinal cells die, says Steven Pittler, Ph.D., senior member of the Vision Science Research Center and professor of Physiological Optics at UAB (University of Alabama at Birmingham). Pittler is a co-author of a study on LCA that was published in a recent issue of The Proceedings of the National Academy of Sciences.

LCA is one of a group of genetic disorders known as retinitis pigmentosa in which genetic malfunctions cause the retina in the eye to deteriorate over time — initially causing night-blindness and often resulting in total blindness. LCA is the most severe form of retinitis pigmentosa. It occurs in early childhood and affected infants are usually born without sight or with very rapidly progressing blindness.

By using oral doses of a vitamin A derivative called 9-cis-retinal, researchers were able to bypass the part of the eye that malfunctions in LCA and restore visual function in 8- to 12-week-old mice who were genetically altered to exhibit a form of the disease. Using an electroretinogram (ERG), a diagnostic tool that measures visual function, researchers found that treated mice experienced a profound restoration of vision. By comparison, untreated mice of the same age have ERG readings indicating very little or no vision.

Researchers were able to develop the treatment by first identifying defective genes that somehow play a role in the disease. Once the genes were identified, researchers developed the genetically-altered mouse model and then developed a treatment to compensate for the genetic dysfunction. Pittler says that this same process could be used to develop treatments for other degenerative genetic disorders.

In a normal eye, a protein called rhodopsin enables the eye to translate light into the electrical signals that the brain interprets as vision. The renewable action of rhodopsin is enabled by a protein made by a specific gene, RPE65. The gene plays another key role by helping to eliminate waste products from used rhodopsin that build up in the eye. Without elimination, a buildup of such waste products eventually causes cells within the retina to die. In an eye with LCA, the elimination action of RPE65 is inhibited because of a mutation within that gene.

Once researchers identified the RPE65 gene as the culprit, they administered a manufactured version of 9-cis-retinal to the mice models. The drug was able to overcome the effects of the RPE65 gene, allowing the mouse's retina to produce an artificial rhodopsin that restored vision.

But Pittler says there is still much work to be done. While the artificial rhodopsin did temporarily restore vision, it did not prevent waste products from building up in the retina. "So our next step is to figure out how to clear the retinal field," Pittler says. "It begs for more research. We probably want to come up with a compound drug that has two components — one component that restores function like the 9-cis-retinal does and one that blocks the accumulation of waste products in the eye."

This study only examined the restoration of visual function for 48 hours. Further studies will look at long-term effects of 9-cis-retinal. "It's nice that we can restore vision and give people two days of great vision, but obviously we need to extend their functional vision for much longer periods," Pittler says. Despite the short duration of the effects of treatment, Pittler says the work could lead to a cure. "I think it's a major discovery, and it's very encouraging."

Pittler has spent 16 years studying retinitis pigmentosa and LCA. In his research, he has identified and isolated five different genes that cause retinitis pigmentosa and he and his team were the first to identify defects in genes that cause LCA. There are now five known genes that cause LCA including the RPE65 gene.