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Trigger Identified for a Form of Macular Degeneration

Penn researchers have identified the underlying cause of Best disease, also known as vitelliform macular dystrophy. Best affects children and young adults and can cause severe declines in central vision as patients age.

The research team used an animal model of Best disease in combination with biochemical and optical assays to identified the abnormalities that lead to the impairments, including vision loss, caused by Best disease.

The study was published in the journal Progress in Retinal and Eye Research.

​​​​​​​“The genetic cause of the disease has been known for 20 years, but no one had samples of patients at the stage when the disease starts,” said Karina E. Guziewicz, research assistant professor of ophthalmology in Penn’s School of Veterinary Medicine and lead author of the study. “But we were now able to pinpoint this early stage and find out what factors trigger the development of lesions.”

The study revealed the reason vision loss in people with Best disease impacts only the macula fovea, the central areas of the retina responsible for reading and tasks requiring high-resolution vision. They found the problem relates to the supporting structures of rods versus cones. Rods are supported by RPE microvilli — which cup cells like stakes holding up plants —  while cones are supported by both a sheath of microvilli that engulfs the cells and an insoluble matrix. When the researchers examined the canine macula of dogs affected with the canine equivalent of Best disease, they found that the microvilli don’t form and that the matrix is fragmented. The loss of the matrix leads to disease.

In experiments conducted in collaboration with David Gamm’s laboratory from the McPherson Eye Research Institute at the University of Wisconsin-Madison, the researchers found similar signatures in at human induced pluripotent stem cell-derived RPE from Best disease patients.

The study findings will allow the researchers to begin testing a gene therapy to treat the disease with a goal of correcting these structural and biochemical abnormalities.

“Now that we understand what we’re seeing, it allows us to judge the success of a particular therapy,” said Gustavo Aguirre, professor of medical genetics and ophthalmology at Penn Vet.

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