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

持续递送 linomiide-5 治疗糖尿病视网膜病变和黄斑变性

• 批准号: 7405172
• 负责人: Rafal A Farjo
• 金额: $ 72.9万
• 依托单位: CHARLESSON, LLP
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7405172
• 关键词: Acute; Address; Age related macular degeneration; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Diseases; Autopsy; Blindness; Blood; Blood Vessels; Blood capillaries; Blood-Retinal Barrier; Caliber; Choroidal Neovascularization; Clinical; Clinical Trials; Collection; Contracts; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Dose; Drug Formulations; Drug Kinetics; Encapsulated; Enzyme-Linked Immunosorbent Assay; Event; Exhibits; Extravasation; Eye; Family suidae; Future; Goals; High Pressure Liquid Chromatography; Histology; Histopathology; Human; Immunoblotting; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Intercellular adhesion molecule 1; Lasers; Leukocytes; Leukostasis; Liquid substance; Long-Term Effects; Longevity; Measures; Mediating; Microscopic; Modeling; Monocyte Chemoattractant Protein-1; New Drug Approvals; Oryctolagus cuniculus; Pathogenesis; Patients; Perfusion; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Plasma; Play; Prevalence; Prevention; Public Health; Rate; Rattus; Reporting; Retina; Retinal; Retinal Diseases; Retinal Edemas; Role; Roquinimex; Safety; Standards of Weights and Measures; Streptozocin; Sus scrofa; Symptoms; TNF gene; Therapeutic; Tissues; Toxic effect; Tracer; Tumor Necrosis Factor-alpha; United States Food and Drug Administration; Vascular Endothelial Growth Factors; Vascular Permeabilities; Visual; Water; Wit; absorption; analog; angiogenesis; capillary; combinatorial; commercialization; cytokine; day; desire; diabetic; diabetic rat; fluorescein isothiocyanate bovine serum albumin; in vitro Model; in vivo; macula; macular edema; methyl group; mouse model; nanoparticle; neovascularization; novel; prevent; retina blood vessel structure; retinal ischemia; sex; tumor; vascular inflammation; Acute; Address; Age related macular degeneration; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Diseases; Autopsy; Blindness; Blood; Blood Vessels; Blood capillaries; Blood-Retinal Barrier; Caliber; Choroidal Neovascularization; Clinical; Clinical Trials; Collection; Contracts; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Dose; Drug Formulations; Drug Kinetics; Encapsulated; Enzyme-Linked Immunosorbent Assay; Event; Exhibits; Extravasation; Eye; Family suidae; Future; Goals; High Pressure Liquid Chromatography; Histology; Histopathology; Human; Immunoblotting; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Intercellular adhesion molecule 1; Lasers; Leukocytes; Leukostasis; Liquid substance; Long-Term Effects; Longevity; Measures; Mediating; Microscopic; Modeling; Monocyte Chemoattractant Protein-1; New Drug Approvals; Oryctolagus cuniculus; Pathogenesis; Patients; Perfusion; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Plasma; Play; Prevalence; Prevention; Public Health; Rate; Rattus; Reporting; Retina; Retinal; Retinal Diseases; Retinal Edemas; Role; Roquinimex; Safety; Standards of Weights and Measures; Streptozocin; Sus scrofa; Symptoms; TNF gene; Therapeutic; Tissues; Toxic effect; Tracer; Tumor Necrosis Factor-alpha; United States Food and Drug Administration; Vascular Endothelial Growth Factors; Vascular Permeabilities; Visual; Water; Wit; absorption; analog; angiogenesis; capillary; combinatorial; commercialization; cytokine; day; desire; diabetic; diabetic rat; fluorescein isothiocyanate bovine serum albumin; in vitro Model; in vivo; macula; macular edema; methyl group; mouse model; nanoparticle; neovascularization; novel; prevent; retina blood vessel structure; retinal ischemia; sex; tumor; vascular inflammation

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.

描述（由申请人提供）：Linomide是已知的抗炎药。最近，我们合成了Linomide，Linomide-5的新类似物。该建议的目的是开发Linomide-5作为治疗糖尿病性视网膜病（DR）和与年龄相关的黄斑变性（AMD）的治疗性。这些疾病共同构成了全球失明的主要原因。在这两种情况下，视网膜炎症都是血液 - 视网膜屏障崩溃的原因，这导致血浆和液体渗入视网膜中，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疗法来治疗疾病的炎症和视网膜血管泄漏。在第一阶段的研究中，我们表明Linomide-5在其抗炎活性中比Linomide高约70倍。此外，我们已经证明了该化合物可有效减少多个体内和体外模型的血管泄漏和炎症。为了开发具有持续释放的商业可行治疗，我们将Linomide-5打包到纳米颗粒（L5-NP）中。该建议的目的是评估L5-NP在防止炎症，血管泄漏和DR和AMD动物模型中视力丧失的功效。此外，我们将对兔子和猪进行严格的毒性和药代动力学研究，以评估在未来人类临床试验中使用L5-NP的安全性。这些研究的完成将提供足够的数据，使我们能够向食品药品监督管理局提出调查新药应用。我们预计L5-NP将在治疗DR和AMD方面很有用，并且可以证明是与其他当前批准的抗血管生成药物的组合疗法。公共卫生相关性：视网膜炎症和血管泄漏或血液 - 逆转录屏障的分解是糖尿病性视网膜病变（DR）和与年龄相关的黄斑变性（AMD）的早期特征，可导致黄斑水肿，并导致随后的视力丧失。当前，尚无有效的药物治疗来解决这些疾病中的血管泄漏和炎症。在此II阶段项目中，我们将进一步研究Linomide-5（一种新的抗炎药物候选者）作为治疗这些疾病的治疗方法，并确定其长期疗效，毒性和药代动力学，以获取未来人类临床试验的基本数据。