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Colleen M. McDowell, Tomi Luan, Cameron Millar, Iok-Hou Pang, Robert J. Wordinger, Abbot F. Clark; A New Mouse Model of Human Primary Open-Angle Glaucoma. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2440.
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Elevated intraocular pressure (IOP) is a causative risk factor for the development and progression of glaucoma. Glaucomatous mutations in Myocilin (MYOC) damage the trabecular meshwork and elevate IOP in humans and in mice. Animal models of glaucoma are important to discover and better understand molecular pathogenic pathways and test new glaucoma therapeutics. Although a number of different animal models of glaucoma have been developed and characterized, there are no true models of human POAG. The overall goal of this work is to develop the first mouse model of POAG using human POAG relevant transgene (i.e. mutant MYOC) expression in mouse eyes to elevate IOP and cause glaucomatous optic neuropathy and retinopathy in mice.
Three mouse strains (BALB/cJ, A/J, and C57BL/6J) were used in this study (n=16-18 mice per group). Ad5.MYOC.Y437H (2 uL of 5 X 107 pfu) was injected intravitreally in one eye, with the uninjected contralateral eye serving as the control eye. Conscious IOP measurements were taken using a TonoLab rebound tonometer. Optic nerve damage was assessed using the optic nerve damage score of PPD stained optic nerve cross sections.
Intraocular administration of viral vector Ad5.MYOC.Y437H caused a prolonged, reproducible, and statistically significant IOP elevation in BALB/cJ, A/J, and C57BL/6J mice. IOPs increased to approximately 25 mm Hg in all 3 mouse strains for 8 weeks (p<0.0001). IOPs were stable (12-15 mm Hg) in the uninjected control eyes. We also determined whether there were any strain differences in pressure-induced optic nerve damage. Even though IOP was similarly elevated in the three strains tested (BALB/cJ, C57BL/6J, and A/J ) only the A/J strain had considerable and significant optic nerve damage at the end of 8 weeks with optic nerve damage scores (ONDS) > 3 (p<0.001) in the injected eye.
These results demonstrate that intravitreal injections of Ad5.MYOC.Y437H in A/J mice cause elevated IOP and glaucomatous optic neuropathy; thus providing a new mouse model of human POAG. These data represent a valuable resource for studying the molecular mechanisms and pathophysiology of POAG.
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