Sphingosine Kinase Inhibitors as Anti-Retinopathy Agents

描述（由申请人提供）：该项目的目标是开发新的人鞘氨醇激酶（SK）抑制剂，作为视网膜和脉络膜血管疾病的有效治疗剂。由于其在鞘脂代谢中的关键作用，我们已经将SK作为一种创新的分子靶点，用于开发治疗与过度血管生成相关的眼部疾病的新药。鞘脂越来越被认为是应激反应、细胞分化和增殖的关键介质，并介导血管内皮生长因子（VEGF）和肿瘤坏死因子-a （TNFa）的作用，这两种因子在眼病中起着至关重要的作用。我们假设视网膜内皮细胞内SK响应VEGF而产生的鞘鞘醇-1-磷酸（S1P）对导致血管渗漏和新生血管的级联事件至关重要，而血管渗漏和新生血管是眼病的标志性病理。因此，SK是开发新的治疗药物的关键分子靶点。由于SK在调节增殖中的关键作用，我们正在开发SK抑制剂用作治疗眼病的药物。在该项目的I期研究中，我们证明了我们专有的SK抑制剂可以阻断人视网膜内皮细胞中由VEGF和TNFa诱导的信号通路。重要的是，我们进一步证明，在两种动物模型中，给予我们的SK抑制剂可以减少血管渗漏，包括vegf诱导的裸鼠皮下模型和stz治疗的3个月大的糖尿病视网膜病变模型。两种模型均未观察到对动物的毒性。这些研究提供了SK抑制剂可能有效治疗眼病的第一个原理证明。在这个II期项目中，我们将评估SK抑制剂在另外两种眼部疾病的体内模型中的治疗活性，包括氧诱导视网膜病变和激光诱导脉络膜新生血管。此外，我们将确定眼病模型动物的最佳治疗计划。最后，将完成fda要求的研究，以便提交SK抑制剂ABC294640的临床新药申请。以下具体目标将被解决：1)目的评价ABC294640对氧致视网膜病变模型的保护作用。2)。探讨ABC294640对激光诱导脉络膜新生血管模型的保护作用。3)。完成ABC294640的cGMP合成和ind导向毒理学研究。总的来说，提出的研究代表了一种评估SK抑制剂ABC294640并将其推向眼科疾病治疗临床试验的重点方法。这将为这一创新分子靶点的首个同类抑制剂提供快速评估。

DESCRIPTION (provided by applicant): The goal of this program is to develop novel inhibitors of human sphingosine kinase (SK) that are effective as therapeutic agents for retinal and choroidal vascular diseases. Because of its critical role in sphingolipid metabolism, we have focused on SK as an innovative molecular target for the development of new drugs for the treatment of ocular diseases associated with excessive angiogenesis. Sphingolipids are being increasingly recognized as key mediators of stress responses, cell differentiation and proliferation, and are known to mediate the effects of vascular endothelial growth factor (VEGF) and tumor necrosis factor-a (TNFa) that are of central importance in eye disease. We hypothesized that sphingosine-1-phosphate (S1P) produced by SK within retinal endothelial cells in response to VEGF is critical to the cascade of events that results in the vascular leakiness and neovascularization that are hallmark pathologies in eye disease. Therefore, SK is a key molecular target for the development of new therapeutic agents. Because of the pivotal role of SK in regulating proliferation, we are developing SK inhibitors to be used as drugs to treat eye disease. In Phase I of this program, we demonstrated that our proprietary SK inhibitors block signaling pathways induced by VEGF and TNFa in human retinal endothelial cells. Importantly, we further demonstrated that administration of our SK inhibitors reduces vascular leakiness in two animal models, including a VEGF-induced subcutaneous model in nude mice and a 3-month diabetic retinopathy model in STZ-treated rats. No toxicity to the animals was observed in either model. These studies provide the first proof-of-principle demonstration that SK inhibitors are likely to be effective in the treatment of eye disease. In this Phase II project, we will evaluate the therapeutic activity of the SK inhibitor in two additional in vivo models of ocular disease, including oxygen-induced retinopathy and laser-induced chorodial neovascularization. Additionally, we will determine the optimal schedule for treatment of the animals in the eye disease models. Finally, FDA-required studies will be completed to enable the submission of an Investigational New Drug application for the SK inhibitor ABC294640. The following Specific Aims will be addressed: 1.) To evaluate the protective effects of ABC294640 in a model of oxygen-induced retinopathy. 2.) To evaluate the protective effects of ABC294640 in a model of laser-induced choroidal neovascularization. 3.) To complete cGMP synthesis and IND-directed toxicology studies with ABC294640. Overall, the studies proposed represent a focused approach to evaluate and move the SK inhibitor ABC294640 into clinical trials for the treatment of ocular disease. This will provide rapid evaluation of the first-in-class inhibitor of this innovative molecular target.