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Karen Yud Torrejon, Andrea Unser, Feryan Ahmed, Vandhana Chari, Thurein Htoo, Cynthia Steel, Barbara M Wirostko; Use of a Novel Potassium Channel Opener in a 3D-Glaucomatous Human Trabecular Meshwork/Schlemm’s Canal Tissue Model. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2758.
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Simulating glaucoma pathology and medication-induced changes to the anatomy and physiology of the conventional outflow pathway presents a unique challenge. In this study, we utilized our proprietary 3D-bioengineered glaucomatous conventional outflow model to investigate the ability of QLS-100 to modulate outflow in vitro. QLS-100 is the active moiety of QLS-101, a novel KATP channel opener with the unique ability to enhance outflow in the absence of ocular side effects such as hyperemia. The effects of QLS-100 on fibrotic and endothelial junctional markers in human trabecular meshwork/Schlemm’s canal co-cultures are also described.
Bioengineered 3D conventional outflow tract constructs, using 4 donors (ages 47-91), were treated with TGFβ-2 (5 ng/mL) for 6 days. Constructs were then treated with QLS-100 (1, 10 or 100μM), or Y-27632 (10μM). The effect of QLS-100 (1 μM) on outflow facility (hydraulic conductivity) was assessed by perfusion studies where pressure was constantly recorded at various perfusion rates. Protein expression of a-smooth muscle actin (α-SMA), CD31, endothelin-I, fibronectin, VE-cadherin, Phospho- and total eNOS was analyzed via western blot. Cellular expression of α-SMA, fibronectin, Phospho- and total eNOS was determined by immunocytochemistry and confocal microscopy. Statistical significance was determined by one-way ANOVA with a Tukey’s multiple comparisons test, or by two-way ANOVA.
QLS-100 significantly increased outflow facility across all donors, as compared to TGF-β2 or Y-27632 treated donors (P<0.0001 and P<0.05, respectively). QLS-100 did not affect expression of the cell adhesion proteins CD31 and VE-Cadherin, while Y-27632 significantly decreased their content (P<0.01). Neither compound altered protein expression or distribution of endothelin, fibronectin, α-SMA, or phospho- or total eNOS.
QLS-100 significantly improved outflow facility in glaucomatous tissue constructs without impacting protein expression of fibrotic or endothelial junctional markers. Y27632 decreased expression of endothelial junctional markers, which may explain the hyperemia observed with clinical ROCK inhibition. These results indicate that the novel prodrug QLS-101 is a promising treatment that may lower elevated IOP without altering vessel integrity.
This is a 2021 ARVO Annual Meeting abstract.
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