May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
CLT-005, A Novel Stat3 Inhibitor for Treatment of Retinal Inflammation and Neovascularization
Author Affiliations & Notes
  • R. Farjo
    Research and Development, Charlesson, Oklahoma City, Oklahoma
  • D. Nuno
    Research and Development, Charlesson, Oklahoma City, Oklahoma
  • J.-X. Ma
    Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
  • Footnotes
    Commercial Relationships  R. Farjo, Charlesson, E; Charlesson, P; D. Nuno, Charlesson, E; J. Ma, Charlesson, C.
  • Footnotes
    Support  NIH/NEI 1R43EY018989-01
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 1373. doi:https://doi.org/
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    • Get Citation

      R. Farjo, D. Nuno, J.-X. Ma; CLT-005, A Novel Stat3 Inhibitor for Treatment of Retinal Inflammation and Neovascularization. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1373. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Activation of signal transducer and activator of transcription 3 (Stat3) has been observed during pathogenic angiogenesis and inflammation. The goal of this study is to establish preclinical efficacy for a novel small molecule inhibitor of Stat3, CLT-005, in reducing retinal inflammation and neovascularization.

Methods: : Primary bovine retinal capillary endothelial cells and pericyte cultures were treated with varying doses of CLT-005 and subjected to MTT assays to determine the effect on cell viability. Brown Norway rats were given an intraperitoneal injection of streptozotocin to induce diabetes, and blood glucose levels were monitored for two weeks. Multiple groups of diabetic and non-diabetic rats received an intravitreal injection of 50 ng or 5 µg CLT-005 in one eye, and the vehicle alone in the contralateral eye as a control. At 24 hrs following injection, qRT-PCR was performed to examine the effect of Stat3 inhibition on the expression of multiple genes involved in retinal inflammation and neovascularization. At 2 days post-injection, the effect on retinal vascular leakage was measured using FITC-albumin as the tracer dye and the protein levels of several inflammatory and angiogenic proteins were quantified with Elisa.

Results: : At micromolar doses, CLT-005 has potent and dose-dependent effects on reducing endothelial cell viability without producing detectable adverse effects in pericyte cells at the same concentrations used. Intravitreal administration of CLT-005 was well-tolerated and reduced the mRNA expression of TNF-α, MCP-1, ICAM-1, LRP-5, and LRP-6 near to the baseline levels observed in non-diabetic rats. For a majority of the genes examined, the 50 ng dose was as equally effective as the 5 µg dose in reducing mRNA levels. No significant change in the expression of phototransduction genes, such as rhodopsin and rod-transducin were observed in any of the samples examined. Elisa analyses demonstrated a dose-dependent decrease of VEGF and ICAM-1 protein levels following intravitreal administration of CLT-005.

Conclusions: : These initial studies demonstrate that CLT-005 is effective in reducing the expression of numerous factors involved in pathogenic inflammation and neovascularization in the retina. The results suggest that CLT-005 may be a suitable therapeutic option for patients with Age-related Macular Degeneration, Diabetic Retinopathy, and Diabetic Macular Edema. Further studies are underway to examine whether CLT-005 is effective in reducing penetrating choroidal neovascularization in a mouse model of AMD.

Keywords: age-related macular degeneration • diabetic retinopathy • drug toxicity/drug effects 
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