Fresh insights into genes and macular degeneration could open new treatment pathways

NIH researchers have pinpointed 6 genomic regions that are closely associated with the development of age-related macular degeneration. (Pixabay)

The National Institutes of Health's National Eye Institute (NEI) has been actively searching for new ways to exploit the genetic underpinnings of age-related macular degeneration (AMD), a leading cause of blindness. Now scientists at the NEI have built on previous research that identified 52 genetic variants significantly associated with AMD. In so doing, they pinpointed AMD-related targets at six different “loci,” or genomic regions.

They believe their findings could generate new ideas for disease-modifying treatments in AMD.

A team led by Anand Swaroop, Ph.D., chief of the Neurobiology-Neurodegeneration and Repair Laboratory at NEI, compared eye tissue from deceased donors, some with AMD and some without the disease. In an earlier project, they identified 34 loci that were associated with AMD—but they didn’t know which of those were actually exerting a biological effect on the disorder.

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So they used computational analysis to compare genes that actively express proteins in the retina with more than 9 million genetic variants that had been identified in previous research. They looked specifically for genetic variants that were most likely to create variations in gene expression in people with and without AMD, according to a statement. That’s how they narrowed down the range of target loci from 34 to six.

The NEI researchers pointed to two genes, B3GLCT and BLOC1S1, as potential drug targets in AMD, because they appear to affect functions such as the disposal of unwanted proteins in the eye. What’s more, the NEI team found three AMD-related genes that had never been associated with the disease before, they reported. Their findings were published in the journal Nature Genetics.

“Importantly, the ability to define how genetic variation affects gene expression opens up entirely new directions for looking at the biology of the eye,” Swaroop said in the statement.

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Due to the rate of aging in the population, the number of Americans with AMD jumped 18% in the first decade of this century to more than 2 million. That number is expected to soar past 5 million by 2050, according to the NEI, making the need for new approaches to prevent and treat the disease all the more pressing.

The NEI is pursuing several approaches for combating the disease, including a stem cell therapy that it recently started testing in people. It is aimed at replacing light-sensing retinal pigment epithelium (RPE) cells in the hopes of preventing vision loss that’s caused by AMD. In animal studies, patches of RPE cells made from stem cells expressed the RPE65 gene, which was critical for reversing degeneration of the retina.

Several other regenerative approaches to treating AMD are being examined, including a gene therapy from Regenxbio. It delivers a gene aimed at neutralizing VEGF, a protein that stimulates the growth of the leaky blood vessels in the eye that cause the “wet” form of AMD. And last year, University of Birmingham scientists reported encouraging results from an animal study of an eye drop that they hope will be able to replace the anti-VEGF injections that are used now to treat AMD.

Swaroop’s team at the NEI has been building a database that they hope will further their research—and that of all scientists working on eye diseases. The resource, called EyeGEx, is a database of retinal gene expression.

Swaroop and his colleagues are now planning further studies aimed at explaining how the new genes they identified influence the development of AMD, and to search for new treatment strategies.