Research Highlight March 29, 2022

Shedding light on new treatments for eye disease

A rendering of an eyeball in blue overlaid with data points representing scientific research

The eyes may be the window to the soul, but the laboratory mouse is the window to the eyes.

To understand human eye diseases, researchers look to the mouse. “Mouse models are uniquely suited for studying eye diseases that occur in people, says Jackson Laboratory Professor Patsy Nishina, Ph.D.Employs mouse models of human eye disease to study gene function and mechanisms underlying disease pathology.Patsy Nishina .

“Many of the disease characteristics that occur in human patients are also observed in the mouse,” she says. “We can develop mice with the same genetic profile as patients, so we can find therapies to target the pre-symptomatic stage to prevent, delay onset or decrease severity of the disease.”

Over the past decade, Nishina and her colleagues including Bo Chang, Ph.D.Conducts research to identify, characterize, and distribute mice with genetically caused eye disorders, including retinitis pigmentosa and achromatopsia.Bo Chang , director of the JAX Eye Mutant Resource, have developed mouse models for translational vision research that are now available to the biomedical research community. Dozens of these mouse models carry genetic variants previously linked to retinal developmental or degenerative ocular disease.

Nishina notes that thanks to the relatively short lifespan of a mouse — about two years in laboratory care — and the ability to control the environmental factors that may contribute to eye diseases, researchers can do detailed, longitudinal studies that reveal how the diseases progress.

Nishina, whose research focuses on heritable retinal disorders, collaborates with her husband, Professor Jurgen Naggert, Ph.D.Researches the complex genetics of metabolic syndrome, involving obesity, cardiovascular disease and type 2 diabetes.Juergen Naggert , The Nishina-Naggert research team recently obtained a five-year grant totaling $2,960,900 from the National Eye Institute to study retinal diseases that arise from mutations in the CRB1, a gene important in retinal development.

The retina is the structure at the back of the eye that processes visual information. When someone emails you a jpeg, it’s not an image until you open it on your computer. Likewise, the eyes detect light and deliver the information to the brain, which does the job of interpretation.

To get to the retina, light reflects off an object and enters the clear, window-like outer part of the eye, the cornea. Next it travels through the fluid of the anterior chamber to the pupil, the dark circle in the middle of the iris, which is the colored part of the eye that controls how big the pupil is (contracting in the presence of bright light, expanding in dim). Behind the pupil is the lens of the eye, which changes shape when your focus shifts between distant and nearby objects.

Finally, light reaches the retina. It’s made up of millions of photoreceptors — rods and cones — and other cells, packed into a three-layer film only half a millimeter thick over the surface of the back of the eye. These cells convert light into electrical signals that travel along the optic nerve, a bundle of about a million nerve fibers, to the brain.

Of the million or so American adults who are blind, heritable retinal disorders account for an estimated 20 to 25 percent. Blindness is much rarer among children, but among the three percent of Americans under age 18 whose vision is nearly or completely impaired, the heritable disease Leber congenital amaurosis causes one in five cases, 10 to 15 percent of which involve mutations in the CRB1 gene. CRB1 mutations can also cause congenital or early-onset retinitis pigmentosa, and have been associated with other eye-disease symptoms.

Nishina is studying the mechanisms that underlie CRB1-associated retinal diseases. “To develop effective therapies for rare diseases caused by single-gene mutations,” she says, “it’s extremely important to know both genetic context and environmental factors that might influence disease development. These factors, which may alter disease onset, severity and clinical appearance, may thereby alter response to treatments.”

Identifying these genetic and environmental “modifiers,” she explains, promises to deepen our understanding of disease mechanisms, yield new potential targets for therapeutic intervention, and enhance the use of precision medicine to improve treatments.

Naggert conducts research in an eye structure known as the external limiting membrane, which could hold the key to understanding and treating enhanced S-cone syndrome (ESCS), diabetic retinopathy and other diseases of the retina.

The adult human retina has about 120 million rods and 6 million cones. Cones come in three subtypes according to the wavelength of light they process: short (S), medium (M) and long (L). In a normal retina the S cones make up just 10 percent of cones, but in ESCS they are the most populous subtype. This causes dysplasia (deformation) of the retina and progressive degeneration of photoreceptors, leading to early night blindness and loss of visual acuity. 

Exploiting modifiers

“ESCS is a rare disease caused by mutations in a gene, NR2E3,” says Naggert. “There is quite a bit of variability in the severity of the disease in humans. And in mouse models, the amount of degeneration varies depending on the genetic background of the mouse carrying the mutation. So it’s clear there are ‘modifier’ genes involved.”

Just as every one of us carries genetic variations that predispose us to different diseases, we also have genes that may mitigate the severity of those diseases. But while these so-called modifier genes offer obvious opportunities for treating all kinds of diseases, the complex genetic interactions involved have been extremely difficult to pin down.

This is where special, genetically varied mouse populations come in. Nishina and other JAX eye researchers are using Collaborative Cross and Diversity Outbred (CC/DO) mice to study eye diseases. The product of carefully orchestrated crosses of inbred mouse strains, these mouse populations reflect even more genetic diversity than the entire human population. So it’s possible to trace the progress of a given eye disease in many individuals, and deduce which additional genes may be contributing to more or less severe disease symptoms.

The mouse and the macula

A leading cause of vision loss in older people is age-related macular degeneration (AMD). According to the National Eye Institute, AMD affects more nearly 3 million Americans, a number that is expected to increase due to the aging of the U.S. population.

AMD disease causes damage to the macula, a small spot near the center of the retina and part of the eye that is necessary for seeing things clearly. Despite the widespread use of laboratory mouse models in the study of glaucoma and many other eye diseases, research in AMD has been hampered because mice aren’t thought to have a macula.

Krebs has discovered that AMD-like pathology in a recently described mouse model is localized to a small area at the back of the eye, which may be related to the macula.

Working with a mouse model of a macular disease known as Researchers link mutations to butterfly-shaped pigment dystrophy, an inherited macular diseaseA butterfly-shaped pigment accumulation in the macula of the eye, which can lead to severe vision loss in some patients, is due to mutations in the alpha-catenin 1 gene (CTNNA1), an international research consortium including a team from The Jackson Laboratory reports in Nature Genetics. butterfly-shaped pigment dystrophy , Krebs observed unusual lesions in a specific area of the retinal pigment epithelium (RPE), a very thin, pigmented cell layer found directly beneath the photoreceptor cells in the retina.

“Our hypothesis is that this area of the mouse posterior eye constitutes a macula-related specialization that develops lesions under conditions associated with human macular disease, including aging,” says Krebs. Nishina and JAX Professor Gregory Carter, Ph.D.Develops computational strategies using genetic data to understand complex genetic systems involving multiple genes and environmental factors.Greg Carter are investigating how disruptions in the RPE can lead to severe vision impairment and loss in AMD and other heritable retinal diseases.

Currently there are no effective cures for AMD or most RPE-related diseases. Previous studies have shown that mouse models of inherited RPE-driven disease often share similar disease features. By examining these models, and using computational tools that the Carter lab is developing, the researchers hope to discover some potential molecular pathways that could be druggable targets.

New approaches to treatment delivery

A longtime goal of genetics research has been to develop safe and effective gene therapy: Directly delivering corrected genes to replace defective versions. Chang was on the research team that, in 2007, reported Gene therapy restores vision to blind miceJAX Research Scientist Bo Chang, M.D., and collaborators have used a gene-based therapeutic approach to restore vision in blind mice with dysfunctional cone cells.the first successful gene therapy to correct cone cell-mediated electroretinogram (ERG) function and restore sight in mice. Since then Chang has collaborated on several other gene therapy projects, including working with researchers at the Icahn School of Medicine at Mount Sinai to regenerate rod photoreceptors in damaged mouse retinas.

“Serious or disabling eye diseases affect many millions of people worldwide,” Chang says. “But research on these diseases is limited by the obvious obstacles to studying disease processes in the human eye. Mouse models of inherited ocular disease provide powerful tools for understanding disease progression, and for designing molecules for translational research and gene-based therapy.”


Genetic Modifiers of Retinal Disease, National Eye Institute, Grant Number 2R01EY027305-05