BAR HARBOR -- Researchers at The Jackson Laboratory have identified the first naturally occurring animal model of subretinal neovascularization, a component of age-related macular degeneration (ARMD) in humans. The discovery provides a powerful investigative tool that could lead to therapies for this devastating eye disease, the leading cause of blindness in people over 50.
The Bst (belly spot and tail) mouse develops subretinal neovascularization (SRN), characterized by an abnormal proliferation of blood vessels beneath the retina. This condition underlies a type of age-related macular degeneration known as the "wet" form, which accounts for only 10 percent of ARMD cases but 90 percent of all severe vision loss from the disease.
"Previous animal models for subretinal neovascularization were artificially induced," says Dr. Richard S. Smith of The Jackson Laboratory. "Our model is the first confirmed occurrence of spontaneous, genetically determined SRN. Now we can look deeper for the genetic basis and molecular pathways of macular degeneration."
The new model is described in "The Bst locus on mouse chromosome 16 is associated with age-related subretinal neovascularization," published today on the website of Proceedings of the National Academy of Sciences. (The article will appear in print in the next issue of PNAS). Dr. Smith is lead author; coauthors are Drs. Simon W.M. John, Muriel T. Davisson, and Bo Chang, with colleagues Adriana Zabaleta and Norman L. Hawes, all of The Jackson Laboratory.
Macular degeneration, estimated to afflict 25-30 million people worldwide, targets the central area of the retina, the layer of light-sensitive cells that line the back of the eye. Known as the macula, this retinal bulls-eye is critical for the fine detail vision required for reading and other "central vision" tasks. Peripheral vision is often unaffected in the early stages of the disease.
In the "wet" form of age-related macular degeneration, the abnormally proliferating blood vessels beneath the retina -- in a region called the choroid -- break and leak fluid that damages the light-sensitive cells of the macula. The disease can progress very rapidly, sometimes in one eye, sometimes in both. The more common "dry" form of ARMD involves a different mechanism: fatty deposits that damage the macular cells. Another type of hereditary macular degeneration targets children and teenagers.
The spontaneous Bst mutation arose in 1977 in the C57BLKS inbred mouse strain at The Jackson Laboratory and was localized to a region on Chromosome 16. The strain has been useful in dermatology research and has long been known for its eye and skeletal defects attributed to developmental delay.
Dr. Smith and his colleagues looked closer at aging Bst mice. They found that focal retinal detachments developed in 19 percent of the mice as they aged. Using miniature measuring technologies, the researchers determined that approximately 80 percent of the affected animals exhibited subretinal neovascularization arising from the choroid and extending into the retina. This previously undetected "angiogenic" phenotype is clearly an aging change, not developmental.
Since mice lack an equivalent of the human macula, and ARMD is a complex disease, the observed SRN cannot be assumed as a direct model for age-related macular degeneration. However, the subretinal neovascularization process in the Bst mouse appears very similar to that in humans, promising insights into the mechanisms involved in the development of SRN and ARMD.
"The variable incidence of SRN suggests that chance effects and subtle environmental factors may interact in the expression of what is likely a complex genetic trait," Dr. Smith says. Future research will involve crossing the Bst mutation onto other genetic backgrounds to potentially increase the incidence of SRN and reveal interacting loci that cause SRN.
The research published in Proceedings of the National Academy of Sciences was supported in part by grants from the National Institutes of Health, The Foundation for Fighting Blindness, and PXE International. Dr. John is an assistant investigator for the Howard Hughes Medical Institute.
Journal
Proceedings of the National Academy of Sciences