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

描述（由申请人提供）：利诺胺是一种已知的抗炎药。最近我们合成了一种新的亚胺胺类似物，亚胺胺-5。该提案的目的是开发亚胺胺-5作为治疗糖尿病视网膜病变（DR）和年龄相关性黄斑变性（AMD）的药物。这些疾病共同构成全世界失明的主要原因。在这两种情况下，视网膜炎症都是导致血视网膜屏障破裂的原因，导致血浆和液体渗漏到视网膜，引起黄斑水肿，这是糖尿病患者和AMD患者视力丧失的主要原因。目前迫切需要开发有效的治疗方法来治疗炎症性和视网膜血管渗漏的疾病。在I期研究中，我们已经证明亚胺胺-5的抗炎活性比亚胺胺强近70倍。此外，我们已经证明了这种化合物在多种体内和体外模型中有效减少血管渗漏和炎症。为了开发商业上可行的缓释治疗药物，我们已经将亚胺酰胺-5包装成纳米颗粒（L5-NPs）。本研究的目的是评估L5-NPs在DR和AMD动物模型中预防炎症、血管渗漏和视力丧失的功效。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，以评估在未来的人体临床试验中使用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研究性新药申请。我们预计L5-NPs将可用于治疗DR和AMD，并可与其他目前批准的抗血管生成药物联合治疗。公共卫生相关性：视网膜炎症和血管渗漏或血视网膜屏障破裂是糖尿病视网膜病变（DR）和年龄相关性黄斑变性（AMD）的早期特征，后者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血管渗漏和炎症在这些疾病。在这个II期项目中，我们将进一步研究一种新的抗炎候选药物亚胺胺-5作为治疗这些疾病的药物，并确定其长期疗效、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.