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Molecular culprits driving most common form of glaucoma discovered

Cell Press

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IMAGE: This is the optic nerve of a patient with primary open angle glaucoma, showing characteristic enlarged cup to disc ratio, excavation and loss of nerve fiber layer. view more

Credit: Image provided by Kang Zhang, MD, PhD

African Americans are particularly prone to developing the most common form of glaucoma--a leading cause of blindness--but how genetics can increase one's risk of getting the disease has been poorly understood. A study published September 10 in Molecular Cell provides the first explanation for how a build-up of pressure within the eye may trigger two risk genes to drive retina cell death and vision loss. This insight could lead to a new class of drugs to treat primary open-angle glaucoma.

"Glaucoma is currently treated by lowering intraocular pressure (IOP); however, lowering IOP can only slow down progression--it does not prevent retinal ganglion cell death and blindness," says senior study author Kang Zhang of the Shiley Eye Institute and Institute of Engineering in Medicine at the University of California, San Diego. "Inhibiting P16 [one of the risk genes] can be an important drug target for treatment of glaucoma."

Primary open-angle glaucoma typically strikes people over 50. Retina ganglion cell death begins slowly and then accelerates until the vision loss is noticeable, but by this point the damage is irreversible. People who possess certain variants of the genes SIX6 and P16 are known to be more susceptible to the disease, which is often characterized (but not always) by an increase in eye pressure.

Zhang, Yizhi Liu--of Sun Yat-sen University--and colleagues in the United States and China now show in a mouse model and human eyes that the SIX6 and P16 genes act together to damage retina ganglion cells, eventually leading to cell death. They also provide evidence that high eye pressure increased expression of P16, therefore linking P16 to the best-known risk factor in glaucoma.

"We were surprised by how important P16 is in this disease process and excited about the prospect of developing a new class of drugs to treat glaucoma, which affects tens of millions of people," Zhang says. "We plan to do some preclinical studies to test the efficacy and safety for treatment of glaucoma with reagents targeting P16, and if they are effective, we may contemplate a human clinical trial in the future."

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This study was primarily supported by the 973 Program, the National Institutes of Health, and the State Key Laboratory of Ophthalmology.

Molecular Cell, Skowronska-Krawczyk and Zhao et al.: "P16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma" http://dx.doi.org/10.1016/j.molcel.2015.07.027

Molecular Cell, published by Cell Press, is a bimonthly journal that focuses on analyses at the molecular level, with an emphasis on new mechanistic insights. The scope of the journal encompasses all of "traditional" molecular biology as well as studies of the molecular interactions and mechanisms that underlie basic cellular processes. For more information, please visit http://www.cell.com/molecular-cell. To receive media alerts for Molecular Cell or other Cell Press journals, please contact press@cell.com.

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