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UK’s Ambati Announces Two Important Findings about Macular Degeneration

Jayakrishna Ambati, an associate professor and vice chair of the UK ophthalmology and visual sciences department, recently announced two discoveries that will impact how physicians treat macular degeneration.

Illustration of eyeAge-related macular degeneration (AMD) is the leading cause of permanent vision loss among the elderly in the United States, where 15 million people have the early “dry” form of macular degeneration. Of those patients, about 10 to 20 percent go on to develop the late-stage or “wet” form of the disease.

The earliest clinical indicator of macular degeneration is the presence of drusen, tiny yellow or white deposits under the retina. Although ophthalmologists have known for some time that these deposits are a risk factor for late-stage AMD, it has been unclear what role they play in the progression of the disease.

Drusen in AMD patients contain components known as complement C3 and C5. Ambati’s research found that the presence of bioactive fragments of these components, known as C3a and C5a, are not only markers of AMD that will develop into the late-stage form of the disease, but that the presence of these components also stimulates the progression of AMD.

In the future, early-stage AMD patients could be screened for C3a and C5a to assess their risk for advanced AMD. Ambati’s lab is currently testing substances to block these fragments to potentially treat “high-risk” drusen.
Ambati’s second discovery focuses on angiogenesis—the formation of new blood vessels from pre-existing vessels—and vascular endothelial growth factor (VEGF). In macular degeneration, vessels grow through angiogenesis, destroying the cells that are required for vision. Scientists have long believed that turning off the source of VEGF would halt angiogenesis and disease progression.

Ambati’s team found that while withdrawing VEGF could halt angiogenesis in some areas, it actually encouraged it in others. This previously unknown effect of VEGF was mediated through activating VEGF receptor 1 and deactivating VEGF receptor 2. Additionally, his team found that a compound known as SPARC (secreted protein, acidic and rich in cysteine) could route VEGF away from receptor 1. So, controlling SPARC levels appears to be the key to controlling angiogenesis in macular degeneration.

These findings have far-reaching implications because angiogenesis is also the process by which other growths spread in the body, including malignant tumors.

The February 14, 2006, Proceedings of the National Academy of Sciences published the drusen research, and the February 1, 2006, Journal of Clinical Investigation published the VEGF research. Both projects were supported by the National Eye Institute.
—Allison Elliot

In Brief section as pdf (3 pages)