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Shelley R Boyd, Xu Zhao, Rahul Joshi, David Baek, Natalie Pankova, Hai Wang; Modulation of innate immunity protects against induction and expansion of Geographic Atrophy (GA) in a rodent model of dry Age Related Macular Degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2014;55(13):1241.
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to determine the efficacy of TMi-018, a repurposed drug in Phase III clinical trial for non-ophthalmic indications, to protect against the development and expansion of GA in a pre-clinical model of dry AMD. TMi-018 modulates the innate inflammatory profile, affecting cytokines and chemokines associated primarily with M1 polarization and disease amplification.
patches of GA were generated in 48 adult Sprague Dawley rats using a model of induced RPE loss, and the posterior pole evaluated by confocal scanning laser ophthalmoscopy (cSLO) and electroretinography (ERG) at baseline and out to 6 months, after which terminal histology was performed. Control animals received intra-vitreal (ITV) injection of saline, and experimental groups received a 50-fold dilution series of TMi-018, provided in 2ul volume. Amplitudes of the bright-flash ERG were recorded. Tissue was evaluated by whole-mount and cross-sectional analysis, with emphasis on RPE presence or loss (RPE65) and cellular and non-cellular markers of the innate immune system (CD68, Iba1, CD163, iNOS, TNFa, MCP-1).
Control animals developed large patches of GA, with preceding changes in cSLO imaging including hyperfluorescent Fundus Autofluorescence; the ERG was extinguished. Histology confirmed profound RPE loss and up-regulation of MCP-1, TNF-a and other pro-inflammatory mediators. In an acute paradigm, TMi-18 dose-dependently reduced the incidence of GA and the size of the patches of GA. At low dose, TMi-18 partially prevented this phenotype, reducing patch size by more than 50%, but without rescuing the b-wave amplitude (p=0.487). At medium dose, GA patch size was reduced by over 80%, and the ERG was not statistically different from normal (p<0.05). At high dose, TMi-18 completely prevented RPE loss and protected the ERG response (p<0.05). Similarly, in a chronic model, TMi-18 reduced or prevented patch expansion in a dose-dependent manner (statistical analysis pending). Histology confirms dose-dependent preservation of the RPE; cytokine profiles are presently under investigation.
the immunomodulatory drug TMi-018 protects against the induction and expansion of GA in a rodent model of dry AMD. As this drug has safely completed Phase III enrollment for non-ophthalmic indications, it has the potential to be re-purposed for the treatment of dry AMD
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