In exfoliation glaucoma, a protein dandruff clogs the outflow pathway for the fluid in our eyes. Scientists have evidence that variants of the same gene that enables us to make connective tissue by crosslinking proteins are associated with this unusual glaucoma

Now they are looking in human eye tissue at a long piece of RNA that helps control the expression of that LOXL1 gene with the idea that it may be a culprit in the destructive pileup of LOXL1 protein inside the eye.

A long-term goal is finding better treatment targets for this glaucoma, which is generally more aggressive and difficult to treat than its more common counterpart, primary open angle glaucoma, says Liu, the vision scientist and human geneticist in the Department of Cellular Biology and Anatomy at the Medical College of Georgia at Augusta University.

"Variants of this gene are associated with the disease in every population we have studied worldwide," Liu says, including Caucasians, blacks in South Africa, the Japanese as well as Southeast Asians in India. They found the expression of LOXL1 consistently elevated early in the disease in every population. Variants are a slight difference in the most usual sequence of letters in the DNA.

They want to know if lncLOXL1 needs one or all these factors to do the damage they think it does. If they block these factors, for example, does the destruction still happen? Liu has already seen that treatment of human eye cells with transforming growth factor beta one impacts the expression of this long, noncoding RNA. Now he is looking at things like what happens to levels of the LOXL1 protein.

They also are looking at the impact of environmental factors like ultraviolet light, since proximity to sunlight, like individuals who live in the mountains of Iceland, is an established risk factor for exfoliation glaucoma.

A handful of years ago, Liu and colleagues at Duke University did a genetic association study—which looked at genetic risk factors—and found that variants of the gene LOXL1 in the noncoding region were associated with exfoliation glaucoma. 

Genetic variants impact on proteins in exfoliation glaucoma

In addition to clogging fluid paths, over time the protein pileup appears to nibble away at the endothelial cells that line blood vessels as well as the pericytes, contractile cells that wrap around the endothelial cells and help give blood vessel walls strength and flexibility. The protein also weakens zonules, transparent tendons that help hold the lens of the eye in place.

Although inflammation contributes to the destruction in exfoliation glaucoma, the immune system often does not eliminate the dandruff-like flakes congesting fluid flow of the eye. The pressure inside the eye soars, and the eyedrops that help the more common open-angle glaucoma by increasing outflow and decreasing fluid production don't work. Surgery to improve outflow often does not work long either.

The current studies are primarily using eye tissue from the lens capsule of 20 patients with exfoliation glaucoma as well as 20 patients who needed cataract surgery and are considered the controls. One thing both populations have in common is they are older, which is when cataracts and symptoms of exfoliation glaucoma both tend to surface.

Liu notes that not everyone with one of the known gene variants develops exfoliation glaucoma and that as with many diseases, it's likely a combination of genes and environment that's causative. The aqueous humor directly provides nutrition to the eye and the invaluable fluid is normally replaced about every 90 minutes.