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R. Li, K. Grant, K. Nelkenbrecher, K. Gibbon, Y. Huang, L. Sojo, P. Margaron; Evaluation of QLT0447 for the Local Treatment of Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1448.
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Novel therapies for the wet form of Age-related Macular Degeneration (AMD) remain to be developed to improve the efficacy of standard treatments. In this study, we were investigating the effects of intravitreally delivered QLT0447, a mTOR inhibitor, on the development of laser-induced choroidal neovascularization (CNV) in rats. The relationship among the pharmacologic and pharmacodynamic properties and the ocular tissue concentrations of QLT0447 in the model were also determined.
Thermal laser infrared light (diode laser 810 nm) at 200 mW for 0.075 seconds was delivered to the fundus of Long Evans rats. A single intravitreal injection of 0.5, 5, 50 or 200 µg QLT0447 was performed immediately after laser photocoagulation. Fluorescein angiography and histology assessment (i.e. the area of CNV and CD31-positive cell count within CNV) were performed on the 14th day after intravitreally injection. Posterior segments were harvested 2 hours, 1, 3, 7 and 14 days post-dosing for pharmacodynamic evaluation and tissue distribution. Protein extracts were immunoblotted for the phosphorylation of S6 ribosomal protein, a biomarker for QLT0447 activity. QLT0447 in tissue extract was determined by a LC-MS/MS method.
QLT0447 at the intravitreal doses of 0.5, 5, and 50 µg reduced the incidence of angiographically active CNV lesions (35%, 95%, and 98% inhibiton) and CNV area (15%, 55%, and 50% reduction respectively) in a dose dependent manner.The number of endothelial cells within the CNV area was decreased by 50-60% reduction, at all tested doses. The three higher doses (5 to 50 µg) suppressed S6 ribosomal protein phosphorylation at all time points, whereas the lowest and least potent dose of 0.5 µg inhibited S6 phosphorylation on the first three days only. This first suggests that the mTOR inhibition may be important for the control of CNV development, and secondly strong inhibition of CNV is achieved when the biomarker is continuously inactivated during the model timecourse. QLT0447 was detected in posterior segments at all time points, except for the dose of 0.5 µg. Preliminary results for the three higher doses indicate that the half-life in the posterior segment is about 2 days, regardless of the dose injected. Correlations between tissue levels and biological activities were also established.
QLT0447 is a potent inhibitor of CNV in a rat model. The concomitant pharmacokinetic and pharmacodynamic assessment allowed the identification of therapeutic concentrations to be achieved in large-eye animal models that will be used for the development of ocular formulations.
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