A novel Stat3 inhibitor for treating retinal inflammation and neovascularization

一种用于治疗视网膜炎症和新生血管形成的新型 Stat3 抑制剂

• 批准号: 7481725
• 负责人: Rafal A Farjo
• 金额: $ 24.13万
• 依托单位: CHARLESSON, LLP
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7481725
• 关键词: Ablation; Acute; Address; Adipocytes; Age; Age related macular degeneration; Albumins; Angiogenic Factor; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Area; Binding; Blindness; Blood; Blood Vessels; Blood capillaries; Blood-Retinal Barrier; Cell Proliferation; Cell Survival; Cells; Choroidal Neovascularization; Clinic; Clinical Research; Complex; Contralateral; Data; Diabetes Mellitus; Diabetic Retinopathy; Dimerization; Disease; Disease Management; Dose; Drug Delivery Systems; Dyes; Elevation; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Event; Extravasation; Eye; Family member; Gene Expression; Genes; Glucose; Goals; Growth Factor; Hormones; Human; Immunoblotting; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Insulin-Dependent Diabetes Mellitus; Intercellular adhesion molecule 1; Interleukin 6 Receptor; Interleukin-6; Intraperitoneal Injections; Ischemia; Leptin; Leukocytes; Leukostasis; Measures; Mediating; Messenger RNA; Modeling; Monocyte Chemoattractant Protein-1; Nature; Oxygen; Pathway interactions; Patients; Peer Review; Perfusion; Pericytes; Permeability; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phosphorylation; Phosphorylation Site; Platelet Factor 4; Play; Prevalence; Proteins; Public Health; Rate; Rattus; Receptor Activation; Retina; Retinal; Retinal Diseases; Retinal Neovascularization; Review Literature; Rodent Model; Role; STAT protein; Series; Serum; Signal Transduction; Solid; Streptozocin; Streptozocin Diabetes; Therapeutic; Tracer; Tumor Necrosis Factor-alpha; Tyrosine; United States Food and Drug Administration; Vascular Endothelial Growth Factors; Vascular Permeabilities; Visual; Week; angiogenesis; base; capillary; cell growth; combinatorial; cytokine; cytokine receptor gp130; day; desire; diabetic; diabetic rat; in vivo Model; inhibitor/antagonist; leptin receptor; macular edema; member; monomer; neovascular; neovascularization; novel; prevent; receptor; receptor expression; research study; retina blood vessel structure; retinal ischemia; small molecule; src Homology Region 2 Domain; tool; transcription factor; vascular inflammation

DESCRIPTION (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 vessel 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 therapies 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 involvement 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 initiates 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 neovascularization, 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 neovascular 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 preliminary 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 effect 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. PUBLIC 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 therapeutic 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 rodent models of diabetes and retinopathy.

描述（由申请人提供）：该提案的目的是检查CLT-005（一种新型的STAT3小分子抑制剂CLT-005）用于治疗糖尿病性视网膜病变视网膜的炎症和血管渗漏的功效。已知视网膜血管形成是由血管内皮生长因子（VEGF）蛋白介导的，并且当前的FDA批准治疗AMD是该蛋白的抑制剂及其信号的能力。这些药物在治疗AMD方面是一个很大的进步，但它们1）无法解决该疾病的炎症性质； 2）在所有AMD患者中都不有效； 3）需要每月注射眼睛以输送药物； 4）只有发生视觉损失才能使用。尽管这些疗法在诊所表现出了希望，但针对新途径的新疗法对于更好的疾病管理和组合治疗选择非常需要。同行评审的文献中的几条证据表明，STAT3参与视网膜炎症和新血管形成：1）在人类中，在糖尿病患者或其他某种形式的视网膜病患者的玻璃体中观察到瘦素水平显着升高。 2）瘦素是一种强生血管生成因子，它启动激活级联反应，导致STAT3的磷酸化/激活（PSTAT3）。 3）PSTAT3是一种转录因子，它促进了几种炎症和新血管基因的表达，例如VEGF。 4）在急性视网膜新血管形成的动物模型中，仅在视网膜的新血管区域观察到PSTAT3。 5）炎性细胞因子IL-6还会导致视网膜中PSTAT3的磷酸化，从而导致脉络膜新生血管形成，并阻止该途径抑制新血管事件。由于PSTAT3可以快速改变细胞基因的表达，并且似乎是这些途径的效应分子，因此我们开发了一个小分子（CLT-005），该分子特别抑制了STAT3的磷酸化和随后的二聚化。在我们的初步数据中，我们已经显示了CLT-005：1）被预测与STAT3的磷酸化位点结合，从而阻止了该转录因子的二聚化和激活。 2）选择性抑制内皮细胞增殖，对周细胞活力没有任何强大影响； 3）在糖尿病大鼠模型中降低视网膜ICAM-1和VEGF水平。基于这些有希望的数据，我们建议进一步评估CLT-005在减少视网膜炎症和血管通透性中的疗效中，在糖尿病和视网膜病变的啮齿动物模型中。在此阶段I建议中，我们将授予对糖尿病大鼠眼睛的CLT-005进行不同浓度，并量化促炎性细胞因子IL-6，TNF-1和MCP-1的水平。我们还将评估和量化这些视网膜中的白细胞，作为炎症的早期标志。此外，我们还将量化CLT-005在减少糖尿病大鼠眼中血管泄漏以及氧诱导的视网膜病变的大鼠模型中的疗效，该视网膜病变呈现出急性视网膜新生血管形成。如果该阶段I项目证明了功效，那么这些实验将为II期研究奠定坚实的基础，以进一步证实CLT-005作为视网膜炎症和黄斑水肿的治疗方法。 PUBLIC 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.我们最近开发了一种新型的小分子（CLT-005），该分子抑制了STAT3的激活，因此作为治疗DR和AMD的理想治疗方法。该提案的目的是证明CLT-005的功效是防止视网膜炎症和血管渗漏在糖尿病和视网膜病变的啮齿动物模型中。