UCI researchers find potential new gene-independent therapy for retinal degeneration

A research team led by the UC Irvine School of Medicine has identified a potential new gene-independent therapeutic strategy for treating the millions of people worldwide who suffer from retinal degeneration, a group of diseases that can lead to vision loss.

The study published today online in the Proceedings of the National Academy of Sciences revealed that mice with a mutation in the Nr2e3 gene, which is essential for the normal development of rod photoreceptors (cells in the retina that allow us to see in low light), were resistant to retinal degeneration in three different models of the disease. The mutation in Nr2e3 results in the expression in rods of a subset of genes normally present in cone photoreceptors, the cells in the retina that allow us to see in color and bright light.

"The protective effect of the Nr2e3 mutation in rods is likely driven by the upregulation of one or a few cone genes that are normally suppressed by Nr2e3 in rods,” said lead author Vladimir Kefalov, PhD, UCI professor of ophthalmology and physiology and biophysics. “Our goal is to identify those cone genes that confer the neuroprotective effect observed in Nr2e3-deficient mouse retina. If successful, these experiments will pinpoint novel therapeutic targets for treating photoreceptor degeneration caused by a wide range of mutations.”

Retinal degeneration affects millions of people worldwide and can be caused by mutations in any one of more than 250 genes. Retinitis pigmentosa (RP) is the most common form of retinal degeneration and can result from mutations in dozens of individual genes, most of which are rod-enriched or rod-specific. While rods constitute the great majority of photoreceptors in most mammalian retinas, including mouse and humans, their loss has only relatively mild effects on human visual function, which manifest as night blindness.

The most severe consequence of rod degeneration is secondary cone loss, which occurs via mechanisms that are still actively investigated. The death of cones, which mediate daytime vision, is particularly disabling for patients and represents the primary source of morbidity in RP. Therefore, preventing secondary cone loss is a key goal of therapy for patients with RP.

“The genetic heterogeneity of RP represents a significant challenge for the development of effective treatments for this disease,” said Kefalov. “For this reason, there is a strong motivation to develop gene-independent strategies that could be used to treat a wide range of genetic forms of RP. Our work suggests that we might be able to protect the rods from degeneration by expressing a few cone genes in them, and thus ultimately preserve cone structure and function.”

Kefalov worked with Alexander Kolesnikov, associate project scientist in the UCI School of Medicine, and researchers from the Washington University School of Medicine on this study.

This work was supported by a grant from the Washington University Hope Center for Neurological Disorders and NIH grants EY033810 and EY030075, with additional support from the UC Irvine Gavin Herbert Eye Institute’s unrestricted grant from Research to Prevent Blindness and from an NIH core grant (EY034070).

Read the full article, “Germline knockout of Nr2e3 protects photoreceptors in three distinct mouse models of retinal degeneration” in the March 5 issue of Proceedings of the National Academy of Sciences.