Sphingosine Kinase Inhibitors as Anti-Retinopathy Agents

描述（由申请人提供）：本项目的目标是开发新型人鞘氨醇激酶（SK）抑制剂，其可有效作为视网膜和脉络膜血管疾病的治疗剂。由于其在鞘脂代谢中的关键作用，我们一直专注于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，并且已知其介导血管内皮生长因子（VEGF）和肿瘤坏死因子-a（TNFa）的作用，这在眼部疾病中具有核心重要性。我们假设SK在视网膜内皮细胞内响应VEGF产生的鞘氨醇-1-磷酸（S1 P）对导致血管渗漏和新血管形成的级联事件至关重要，这些事件是眼部疾病的标志性病理学。因此，SK是开发新治疗剂的关键分子靶标。由于SK在调节增殖中的关键作用，我们正在开发SK抑制剂作为治疗眼部疾病的药物。在该项目的第一阶段，我们证明了我们的专利SK抑制剂阻断了人视网膜内皮细胞中VEGF和TNFa诱导的信号通路。重要的是，我们进一步证明了我们的SK抑制剂的施用减少了两种动物模型中的血管渗漏，包括裸鼠中VEGF诱导的皮下模型和STZ治疗的大鼠中3个月的糖尿病视网膜病变模型。在两种模型中均未观察到对动物的毒性。这些研究提供了第一个原理证明，即SK抑制剂可能有效治疗眼部疾病。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体内模型中的治疗活性，包括氧诱导的视网膜病变和激光诱导的脉络膜新生血管。此外，我们将确定眼病模型中动物治疗的最佳方案。最后，FDA要求的研究将完成，以便提交SK抑制剂ABC 294640的研究性新药申请。以下具体目标将得到解决：（1）。评估ABC 294640在氧诱导的视网膜病变模型中的保护作用。2.）的情况。探讨ABC 294640对激光诱导的脉络膜新生血管的保护作用。3.）第三章完成cGMP合成和IND指导的ABC 294640毒理学研究。总的来说，这些研究代表了一种集中的方法来评估SK抑制剂ABC 294640并将其转移到眼科疾病治疗的临床试验中。这将提供对这种创新分子靶点的一流抑制剂的快速评估。

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.