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Macular degenerations occurs in several forms, all are causes of vision loss. Juvenile or early-onset macular degeneration includes several inherited disorders that can affect children and young adults.
In contrast, age-related macular degeneration (AMD) is the leading cause of blindness for individuals over 65 years of age in developed countries, and its increasing worldwide. Both inherited macular degeneration and AMD lead to the loss of central vision. While therapies exist for some forms of late AMD, and nutritional supplements can slow the progress of early AMD for some patients, improved therapies are needed.
However, on line this week in the journal Human Molecular Genetics, an unexpected finding is reported by Drs. Donita Garland, Rosario Fernandez-Godino, and Eric Pierce of the Ocular Genomics Institute at the Massachusetts Eye and Ear, Harvard Medical School. In mice genetically engineered to have an inherited form of macular degeneration, turning off the animals’ complement system—a part of the immune system—prevented the disease.
The findings are important because they suggest that inherited macular degenerations share common features with AMD. The results also suggest that alterations in the activity of the complement system are involved in the earliest stages of disease creation. This finding has important implications for using drugs to modify the complement system in treating macular degenerations.
The research suggests that complement activation by abnormalities in the extracellular matrix or the scaffold secreted by retinal cells plays an important role in the formation of basal deposits, one of the earliest stages of macular degeneration. Basal deposits are precursors of drusen, which appear as spots in the retina on clinical examination, and are accumulations of proteins and lipids outside the retinal cells; their presence is the first clinical indication of a risk of developing macular degeneration.
For these studies, the investigators created a mouse model of the inherited macular dystrophy Doyne Honeycomb Retinal Dystrophy/Malattia Leventinese (DHRD/ML) which is caused by the mutation in the EFEMP1 gene. This mutation leads to extensive drusen in patients with DHRD/ML, and the gene targeted mice develop extensive basal deposits.
As a first step in their studies, Dr. Garland's group identified the proteins present in the basal deposits of the mice. Like they do in people, these deposits form between the retinal pigment epithelial cells and their basement membrane, which is called Bruch’s membrane and is composed of extracellular matrix. These studies showed that the basal deposits are composed of normal extracellular matrix components that are present in abnormal amounts. This is logical because the EFEMP1 protein is secreted by retinal cells and is thought to be required for maturation of elastin fibers, which are part of Bruch’s membrane.
The proteomic analyses also suggest that the altered extracellular matrix stimulates a local immune response, including activation of the complement system. The complement system is part of our innate immune system, and helps fend off infections, but under certain circumstances can also lead to cell and tissue damage.
The Mass. Eye and Ear team applied the power of mouse genetics to study the role of complement in basal deposit formation, and generated Efemp1R345W/R345W:C3-/- double mutant mice, which have the disease-causing mutation in Efemp1 and also lack the key complement component C3. Without C3, the complement system cannot be activated. In contrast to their single mutant Efemp1-R345W cousins, the double mutant Efemp1R345W/R345W:C3-/- mice did not develop basal deposits, demonstrating that the complement system is required for formation of basal deposits.
The investigators plan to continue their studies to help identify additional treatments to prevent vision loss from macular degenerations.
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About Massachusetts Eye and Ear
Authors: Donita L. Garland, Rosario Fernandez-Godino, Inderjeet Kaur, Kaye D. Speicher, James M. Harnly, John D. Lambris, David W. Speicher, Eric A. Pierce
Journal: Human Molecular Genetics
Original press release: http://www.masseyeandear.org/news/press_releases/recent/Critical_Role_for_