Sustained delivery of linomide-5 for diabetic retinopathy and macular degeneratio

说明(申请人提供)：利诺米特是一种已知的抗炎药物。最近我们合成了一种新的利诺米特类似物，利诺米德-5。这项建议的目的是开发利诺米特-5作为治疗糖尿病视网膜病变(DR)和老年性黄斑变性(AMD)的药物。这些疾病加在一起构成了全世界失明的主要原因。在这两种情况下，视网膜炎症都是血-视网膜屏障破裂的原因之一，后者导致血浆和液体渗入视网膜，导致黄斑水肿，这是糖尿病患者和AMD患者视力丧失的主要原因。迫切需要开发有效的治疗方法来治疗这些疾病的炎症和视网膜血管渗漏。在第一阶段的研究中，我们已经证明了利诺米德-5的抗炎活性几乎是利诺米特的70倍。此外，我们已经证明该化合物在多种体内和体外模型中有效地减少血管渗漏和炎症。为了开发一种商业上可行的缓释治疗药物，我们将利诺米特-5包装成纳米粒(L5-NPs)。该提案的目的是评估L5-NPs在预防DR和AMD动物模型中的炎症、血管渗漏和视力丧失方面的有效性。此外，我们将在兔和猪身上进行严格的毒性和药代动力学研究，以评估在未来的人类临床试验中使用L5-NPs的安全性。这些研究的完成将提供足够的数据，使我们能够向食品和药物管理局提交调查性的新药申请。我们预计L5-NPs将同时用于治疗DR和AMD，并可能被证明是与其他目前批准的抗血管生成药物的联合治疗有用的。公共卫生相关性：视网膜炎症和血管渗漏或血-视网膜屏障的破裂是糖尿病视网膜病变(DR)和老年性黄斑变性(AMD)的早期特征，后者会导致黄斑水肿并导致随后的视力丧失。目前，还没有有效的药物治疗来同时解决这些疾病的血管渗漏和炎症。在这个二期项目中，我们将进一步研究新型抗炎药利诺米特-5作为治疗这些疾病的候选药物，并测定其长期疗效、毒性和药代动力学，为未来的人体临床试验获得必要的数据。

DESCRIPTION (provided by applicant): Linomide is a known anti-inflammatory drug. Recently we have synthesized a new analog of Linomide, linomide-5. The objective of this proposal is to develop linomide-5 as a therapeutic for treating diabetic retinopathy (DR) and age-related macular degeneration (AMD). Together, these diseases constitute the major causes of blindness worldwide. In both cases, retinal inflammation is a causative factor for the breakdown of the blood-retinal barrier, which leads to leakage of plasma and fluid into the retina, causing macular edema which is a leading cause of vision loss in diabetic patients and in patients with AMD. There is a dire need to develop effective therapies to treat both the inflammatory and retinal vascular leakage of the diseases. In Phase I studies, we have shown that linomide-5 is nearly ~70 fold more potent than Linomide in its anti-inflammatory activity. Further, we have demonstrated that this compound is effective in reducing vascular leakage and inflammation in multiple in vivo and in vitro models. Towards the development of a commercially viable therapeutic with sustained release, we have packaged linomide-5 into nanoparticles (L5-NPs). The goal of this proposal is to evaluate the efficacy of L5-NPs in preventing inflammation, vascular leakage, and loss of vision in animal models of DR and AMD. Furthermore, we will perform rigorous toxicity and pharmacokinetic studies in both rabbits and pigs to assess the safety of using L5-NPs in future human clinical trials. The completion of these studies will provide sufficient data that will enable us to file an investigative new drug application with the food and drug administration. We anticipate that L5-NPs will be useful in treating both DR and AMD, and could prove useful as a combinatorial therapy with other currently approved anti-angiogenic pharmaceuticals. PUBLIC HEALTH RELEVANCE: Retinal inflammation and vascular leakage or breakdown of the blood-retina barrier are early features of diabetic retinopathy (DR) and age-related macular degeneration (AMD) that leads to macular edema and causes a subsequent loss of vision. Currently, there are no effective drug treatments that address both vascular leakage and inflammation in these diseases. In this Phase II project, we will further investigate linomide-5, a new anti-inflammatory drug candidate, as a treatment for these diseases and determine its long- term efficacy, toxicity, and pharmacokinetics to obtain essential data for future human clinical trials.