Glaucoma Gene Offers New Treatments For The Disease
Reported February 21, 2011
(Ivanhoe Newswire) — Glaucoma – the second leading cause of blindness in the world – is now thought to run in families. A team of investigators from Vanderbilt University and the University of Florida offer an eye opening finding where they have just identified a novel candidate gene for the most frequent form of the eye disorder, primary open angle glaucoma (POAG). The findings present new insights into glaucoma pathology, which could lead to targeted treatment strategies.
Elevated pressure inside the eye is a strong risk factor for POAG. Pressure increases because of increased resistance to the flow of aqueous humor out of the eye’s front chamber (between the cornea and iris). Current treatments for POAG attempt to reduce intraocular pressure by reducing aqueous humor production or by surgically providing a clear “drain.”
“It has been known for decades that the reason the pressure goes up in POAG is because the outflow pathway for aqueous humor is not working,” which Rachel Kuchtey, M.D., Ph.D., assistant professor of Ophthalmology and Visual Sciences and principal investigator of the current studies, was quoted as saying.
“It seems kind of simple – there’s a decrease in the rate of aqueous humor flowing out of the eye,” which John Kuchtey, Ph.D., research instructor in Ophthalmology and Visual Sciences and first author of the paper, was quoted as saying. “But the basic mechanisms of aqueous humor outflow at the cellular and molecular level – and how they are disrupted in glaucoma – are not understood. It’s a long-standing puzzle in ophthalmology.”
So far, three genes have been associated with human glaucoma, but they account for only a small fraction of cases and have not shed much light on the disease process. The Vanderbilt investigators turned to a model with simpler genetics – a canine model of the disease.
Forty years ago, Kirk Gelatt, V.M.D., from the UF College of Veterinary Medicine, came across a litter of beagles that had a high incidence of glaucoma. The finding suggested to Gelatt that the disease was inherited, and he established a colony of POAG-affected beagles to study treatments for the disease.
In affected beagles, intraocular pressure begins to increase at 8 to 16 months of age, due to increased resistance to aqueous humor outflow. The clinical course of the disease “absolutely resembles human glaucoma,” Rachel Kuchtey said.
The beagles are the only naturally occurring animal model for human POAG.
The Vanderbilt investigators used blood samples to search for genes associated with POAG. They initially narrowed in on a certain spot (locus) on canine chromosome 20, which matched part of human chromosome 19. Previous studies had associated the human region with intraocular pressure, a good sign that they were on the right track, John Kuchtey adds.
Sequencing of the entire canine locus – over 4 million “letters” of DNA – revealed that a gene called ADAMTS10 was the strongest disease-associated candidate. POAG-affected dogs have a single mutation in the gene that encodes a protein involved in processing the extracellular matrix (ECM), the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions.
“There is a lot of evidence that proteoglycans (molecules in the ECM) and matrix remodeling might have something to do with aqueous outflow resistance, and so this gene supports that line of investigation,” John Kuchtey said.
The researchers moreover demonstrated that the gene is highly expressed in the trabecular meshwork – an area of tissue in the eye located around the base of the cornea, near the ciliary body, and is responsible for draining the aqueous humor from the eye via the anterior chamber (the chamber on the front of the eye covered by the cornea).
At this time, the investigators are exploring ADAMTS10’s normal biological functions. They have studies in progress to investigate whether the human ADAMTS10 gene is mutated in human glaucoma. They are optimistic that understanding this gene will open therapeutic possibilities for glaucoma.
“Right now we know that aqueous outflow is impaired in POAG, but we have no way to fix it because we don’t understand how that normally works and what the pathology is in POAG,” Rachel Kuchtey concludes. “If this gene truly plays a role in aqueous outflow regulation, we can begin to look at it — or its molecular partners — as targets for treatments.”
Gene therapy to rescue a defect could furthermore be a possibility. Gene therapy for an inherited form of childhood blindness was first validated in dogs and is now in trial in humans.
Facts on Glaucoma:
• Glaucoma is a group of eye diseases that damage the optic nerve (the bundle of nerve fibers that carries information from the eye to the brain), leading to vision loss and possibly blindness.
• Glaucoma is a leading cause of blindness in the United States. Over 2 million Americans have glaucoma and another 2 million may have the disease and not know it.
• Optic nerve damage usually occurs in the presence of high eye (intraocular) pressure. However, glaucoma can be diagnosed with normal or even lower than normal eye pressure.
• Worldwide, it is estimated that about 66.8 million people have visual impairment from glaucoma, with nearly 6.7 million suffering from bilateral blindness.
• Vision experts believe that half of those affected by glaucoma may not know it, since there are usually no symptoms in its early stages.
• Blindness or low vision affects 3.3 million Americans age 40 and over.?
• Glaucoma is a leading cause of blindness among African Americans and Hispanics in the U.S. Three times as many African Americans have glaucoma than Caucasians, and four times as many are blind. Between the ages of 45 and 64, glaucoma is fifteen times more likely to cause blindness in African Americans than in Caucasians.
• The average direct cost of glaucoma treatment ranges from $623 per year for patients with early stage glaucoma to $2,511 per year for end stage patients.
Public Library of Science (PLoS) Genetics, February 2011