New glaucoma research from the United States and China indicates that a genetic interaction may prove to be a key component in the development and progression of open-angle glaucoma. Although this genetic research has been conducted only with laboratory mice, the concept shows great promise for developing and identifying effective therapies for treating – and even preventing – glaucoma.
Molecular Cell: the Research
The research, entitled P16INK4a [a type of gene] Upregulation [increased response] Mediated by SIX6 [also a type of gene] Defines Retinal Ganglion Cell Pathogenesis [i.e., disease development] in Glaucoma (explained and decoded below), has been published online ahead of print in the September 10, 2015 edition of Molecular Cell, a division of Cell Press. Molecular Cell publishes original, peer-reviewed research in molecular biology, including papers that open new avenues of research, report unexpected findings, or change established thought about biological processes.
The lead authors are Dorota Skowronska-Krawczyk and Ling Zhao, along with a research team representing an interdisciplinary mix of United States- and China-based institutions: Shiley Eye Institute, the Department of Reproductive Medicine, the Institute for Genomic Medicine, and the Howard Hughes Medical Institute from the University of California, San Diego; Sichuan University, Sichuan China; JiaoTong University, Shanghai, China; and Sun Yat-sen University, Guangzhou, China.
About Open-Angle Glaucoma
Glaucoma is a group of eye diseases that damage the optic nerve and is one of the leading causes of vision loss and blindness. Open-angle glaucoma is the most common form of glaucoma.
The eye continuously produces a fluid, called the aqueous (or aqueous humor), that must drain from the eye in order to maintain healthy eye pressure. Aqueous humor is a clear, watery fluid that flows continuously into, and out of, the anterior (or front) chamber of the eye, which is the fluid-filled space between the iris and the cornea. It is the aqueous that helps to bring nutrients to the various parts of the eye.
Aqueous fluid drains from the anterior chamber through a filtering meshwork of spongy tissue along the outer edge of the iris (called the trabecular meshwork), where the iris and cornea meet, and into a series of “tubes,” called Schlemm’s canal, that drain the fluid out of the eye. Problems with the flow of aqueous fluid can lead to elevated pressure within the eye.
In primary open-angle glaucoma (POAG), the filtering meshwork may become blocked or may drain too slowly. If the aqueous fluid cannot flow out of the eye, or flow out quickly enough, pressure builds inside the eye and can rise to levels that may damage the optic nerve, resulting in vision loss.
Most eye care professionals define the range of normal intraocular [i.e., within the eye] pressure (IOP) as between 10 and 21 mm Hg [i.e., millimeters of mercury, which is a pressure measurement]. Most persons with glaucoma have an IOP measurement of greater than 21 mm Hg.
If you have been diagnosed with glaucoma, it is critical that you maintain the eye drop medication regimen prescribed by your eye doctor. In order for the medication to lower your intraocular pressure effectively, consistent daily adherence to your prescribed eye drop regimen is essential.
Vision Loss from Glaucoma
Glaucoma results in peripheral (or side) vision loss initially, and as this field loss progresses, the effect is like looking through a tube or into a narrow tunnel. This constricted “tunnel vision” effect makes it difficult to walk without bumping into objects that are off to the side, near the head, or at foot level.
A living room viewed through a constricted visual field.
Source: Making Life More Livable. Used with permission.
Glaucoma is an especially dangerous eye condition because most people do not experience any symptoms or early warning signs at the onset. Glaucoma can be treated, but it is not curable. The damage to the optic nerve from glaucoma cannot be reversed.
About the Glaucoma Genetic Research
Excerpted from Identified Genetic Interaction Offers Possible New Target for Glaucoma Therapy from Health Canal:
Primary open-angle glaucoma (POAG) is the most common form of glaucoma, affecting more than three million Americans, primarily after the age of 50. Pressure inside the eye … and age are the leading risk factors for POAG, resulting in progressive degeneration of retinal ganglion cells, optic nerve damage and eventual vision loss.
[Editor’s note: Retinal ganglion cells (RGCs), are neurons, or nervous system cells. They are located near the inner surface of the retina and give rise to optic nerve fibers that transmit information from the retina to several regions in the brain.]
Genetics also plays a role. Recent [gene] studies have identified two genes – SIX1-SIX6 and p16INK4a – as strongly associated with POAG. SIX6 is required for proper eye development. P16INK4a irreversibly arrests cell growth, a phenomenon called senescence.
In their new paper, principal investigator Kang Zhang, MD, PhD, professor of ophthalmology and chief of Ophthalmic Genetics at Shiley Eye Institute, and colleagues report that some variants of the SIX6 gene boost the expression of p16INK4a, which in turn accelerates senescence and death of retinal ganglion cells. “We also show that high intraocular pressure in glaucoma increases expression of p16INK4a, making it a key integrator (or combiner) of genetic and environmental risk factors that can result in glaucoma,” said Zhang.
The research findings suggest that inhibiting p16INK4a could offer a new therapeutic approach for glaucoma, which is currently treated by drugs that lower intraocular pressure. “Although lowering intraocular pressure can slow the worsening of the disease, it does not stop it and prevent further cell death or possible blindness,” said [co-author] Robert N. Weinreb, MD.
More about the Research from Molecular Cell
Excerpted from the article discussion, with the full article available online:
Glaucoma is the leading cause of blindness, affecting tens of millions of people worldwide. Despite its prevalence, its etiology and pathogenesis [i.e., development] are poorly understood, and treatment is limited to lowering intraocular pressure (IOP). Despite aggressive IOP-lowering therapies, most patients have progressive loss of visual function, and some eventually become legally blind. The relationship of raised IOP and retinal ganglion cell (RGC) death is poorly understood.
Cellular senescence is a state of irreversible growth arrest. When senescent cells accumulate in the tissue, their impaired function can result in a predisposition to disease development and/or progression. In the present study, we show that SIX6 directly regulates expression of p16INK4a, an indicator of cell senescence and aging. Furthermore, we show that upon acute IOP elevation, p16INK4a expression is upregulated, which, in turn, can be a cause of RGC death.
Our hypothesis can help explain how IOP, the most common risk factor, can cause glaucoma. Moreover, it provides a molecular link between genetic susceptibility and other factors to the pathogenesis [i.e., development] of glaucoma. Our study suggests that cellular senescence plays a critical role in the pathogenesis of glaucoma.
Taken together, our study shows that SIX6 variant increases p16INK4a expression upon increased IOP, which in turn causes RGCs to enter into a senescent state and which may lead to increased RGC death in glaucoma. Our study provides important insights into the pathogenesis of glaucoma and suggests future therapeutic strategies based on targeted inhibition of p16INK4a-induced cell senescence to prevent and treat glaucoma.
Additional Glaucoma Information from VisionAware
- Is Glaucoma a Genetic Disease? Three New Research Projects Pinpoint Six Specific Genes
- How Can We Improve Compliance with Glaucoma Medication Regimens? New Research Advocates Team-Based Care, Similar to Diabetes
- Can Generic Drugs Improve Compliance with Glaucoma Medication Regimens? New Research Says Yes