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J. J. Doyle, A. L. Jun, P. Gehlbach, D. Guyton, H. Quigley, H. C. Dietz; Pharmacological Inhibition of TGFβ Signaling Ameliorates Disease in a Genetic Model of Axial Myopia. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1194.
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© ARVO (1962-2015); The Authors (2016-present)
Myopia is a highly prevalent ocular condition. In the U.S. 25% of adults are myopic (4.5% severely so), with estimates being 3-fold greater in Asia. High myopia is associated with a number of sight-threatening complications that include retinal detachment, macular degeneration, glaucoma, and cataract, all of which may lead to permanent visual impairment or blindness. Early-onset, progressive, and often severe myopia is one of the most prevalent and important ocular manifestations of Marfan syndrome (MFS), a systemic connective tissue disorder caused by mutations in the FBN1 gene. Enhanced TGFβ signaling has been implicated in the pathogenesis of multiple manifestations of MFS, including aortic aneurysm, emphysema and skeletal myopathy. Furthermore, antagonizing TGFβ signaling using TGFβ neutralizing antibody (NAb) or the clinically-available angiotensin type 1 receptor (AT1R) blocker losartan has been shown to ameliorate these phenotypes in MFS mice. We analyzed the role of TGFβ signaling in axial globe elongation in MFS and the potential of its antagonism as a therapeutic strategy for axial myopia, using MFS as a model.
The axial globe length of C1039G/+ Marfan mice was measured using high-power microscopy of OCT-embedded globes sectioned through to the axial midline.
Marfan mice had significantly elongated globes compared to wild-type littermates at 2, 4 and 6 months of age (p=0.002). Since 6 month-old C57BL/6J mice have a focal length close to 2.32mm, the 190um elongation seen in MFS mice at this age corresponds to approximately a 35D change in refractive error. To investigate whether excess TGFβ signaling plays a causal role in this process, we treated mice with TGFβ NAb or placebo (IgG) from 2 to 4 months of age. At 4 months, TGFβ NAb-treated Marfan mice had axial globe lengths that were significantly less than placebo-treated littermates (p=0.007), in fact being indistinguishable from WT. Hence we investigated whether losartan could attenuate axial globe elongation in MFS. Losartan-treated Marfan mice also had significantly smaller globe lengths than placebo-treated littermates at both 2 and 6 months of age (p=0.001), again being indistinguishable from WT.
These data implicate enhanced TGFβ signaling in MFS-associated axial myopia and suggest that its antagonism using TGFβ NAb or losartan are productive therapeutic strategies. The relevance of this signaling pathway and its antagonism using AT1R blockers now warrants exploration in more common presentations of myopia.
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