A novel Stat3 inhibitor for treating retinal inflammation and neovascularization
Small Business Information
CHARLESSON, LLC, 800 Research Parkway, OKLAHOMA CITY, OK, 73104
AbstractDESCRIPTION (provided by applicant): The objective of this proposal is to examine the efficacy of CLT-005, a novel small molecule inhibitor of Stat3, for treating inflammatory and vascular leakage of the retina of diabetic retinopathy. Retinal blood vesse l formation is known to be mediated by the vascular endothelial growth factor (VEGF) protein, and current FDA approved treatments for AMD are inhibitors of this protein and its ability to signal. These drugs are a great advancement in the treatment of AMD, but they 1) fail to address the inflammatory nature of the disease; 2) are not effective in all AMD patients; 3) require monthly injections into the eye to deliver the drug; 4) can only be used once visual loss has already occurred. Although these therapi es have shown promise in the clinic, new treatments that target novel pathways are highly desirable for better disease management and combinatorial therapeutic options. Several lines of evidence in the peer reviewed literature suggest the intimate involvem ent of Stat3 in retinal inflammation and neovascularization: 1) In humans, significantly elevated levels of Leptin are observed in the vitreous of patients with diabetes or some other form of retinopathy. 2) Leptin is a strong pro- angiogenic factor that i nitiates an activation cascade resulting in the phosphorylation/activation of Stat3 (pStat3). 3) pStat3 is a transcription factor that promotes expression of several inflammatory and neovascular genes, such as VEGF. 4) In animal models of acute retinal neo vascularization, pStat3 is observed solely in the neovascular areas of the retina. 5) The inflammatory cytokine IL-6 also causes phosphorylation of pStat3 in the retina which causes choroidal neovascularization, and blockade of this pathway inhibits neovas cular events. As pStat3 can rapidly change cellular gene expression and appears to be the effector molecule of these pathways, we developed a small molecule (CLT-005) that specifically inhibits phosphorylation and subsequent dimerization of Stat3. In our p reliminary data, we have shown the CLT-005: 1) is predicted to bind to the phosphorylation site of Stat3, thus blocking dimerization and activation of this transcription factor; 2) selectively inhibits endothelial cell proliferation without any strong effe ct on pericyte cell viability; 3) reduces retinal ICAM-1 and VEGF levels in a rat model of diabetes. Based on these promising data, we propose to further evaluate the efficacy of CLT-005 in reducing retinal inflammation and vascular permeability in rodent models of diabetes and retinopathy. In this Phase I proposal, we will intravitreally administer varying concentrations of CLT-005 to the diabetic rat eyes and quantify the levels of the pro-inflammatory cytokines IL-6, TNF-1, and MCP-1. We will also assess and quantify leukostasis in these retinas as an early marker of inflammation. In addition, we will also quantify the efficacy of CLT-005 in reducing vascular leakage in the diabetic rat eye and in the rat model of oxygen-induced retinopathy which presents with acute retinal neovascularization. If this Phase I project proves the efficacy, these experiments will lay a solid ground for Phase II studies to further substantiate the promise of CLT-005 as a treatment for retinal inflammatory and macular edema. PU BLIC HEALTH RELEVANCE: Neovascular diseases of the retina, including Diabetic Retinopathy (DR) and Age-related Macular Degeneration (AMD), are the leading cause of blindness worldwide in patients over the age of 50. In several in vitro and in vivo models, activation of Stat3 has been shown to play a major role in initiating inflammatory and neovascular events in the retina. We have recently developed a novel small molecule (CLT-005) that inhibits this activation of Stat3, and thus presents as an ideal thera peutic for treating DR and AMD. The goal of this proposal is to prove the efficacy of CLT-005 is preventing retinal inflammation and vascular leakage in rod
* information listed above is at the time of submission.