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George Inana, Claudius Tapia, Yoshihiro Mizutani, Christopher Murat, Margaret McLaren; Comparison Of Anti-mt1-mmp And Anti-vegf Therapy In Age-related Macular Degeneration (amd) Choroidal Neovascularization (cnv) Model. Invest. Ophthalmol. Vis. Sci. 2011;52(14):947.
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© ARVO (1962-2015); The Authors (2016-present)
We have identified membrane-type matrix metalloproteinase 1 (MT1-MMP) as a candidate gene for AMD by a custom expression profiling strategy called CHANGE based on its 1) over-expression in human AMD eyes, and 2) role in photoreceptor outer segment (OS) phagocytosis by the RPE, a key function and daily burden for the RPE cells which are primarily affected in AMD. We have constructed a proof-of-concept transgenic mouse (Tg) model that conditionally over-expresses MT1-MMP and produces a phenotype similar to that found in both the dry and wet form of AMD, supporting the involvement of this gene in the pathogenesis of AMD. In this study we analyzed the efficacy of antibodies to MT1-MMP and VEGF in suppressing the formation of CNV in the mouse laser photocoagulation model.
Activity-neutralizing antibodies to MT1-MMP or VEGF were intravitreally injected into mouse eyes, and CNV was induced by laser photocoagulation. After 2 weeks, the extent of CNV was analyzed in ocular flatmounts from the mice, taking into consideration both the fluorescence and the size of the lesions (CNV index).
The results of 14 experiments assessing the efficacy of anti-MT1-MMP antibody showed a significant ameliorative effect on CNV formation over the control eye. With untreated control lesions being normalized to a CNV index value of 1.0, the MT1-MMP treatment resulted in a CNV index of 0.52 (p=0.0000015). In 6 of these experiments in which anti-VEGF antibody was compared to anti-MT1-MMP antibody, the effect of anti-VEGF Ab showed no difference from control (CNV index ratio of 1.60 (p=0.07) for anti-VEGF Ab). The difference between the two treatments was statistically significant by the paired test (p=0.016).
Anti-MT1-MMP treatment was shown to be effective against CNV formation in the mouse AMD model, confirming the importance of this gene/protein in the pathogenesis of AMD. The efficacy of CNV suppression by anti-MT1-MMP antibody was superior to that of anti-VEGF antibody in the mouse model. Studies are planned to extend these results in non-human primates.
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