Anti-ceramide immunotherapy for diabetic retinopathy

抗神经酰胺免疫疗法治疗糖尿病视网膜病变

基本信息

批准号：
10440369
负责人：
Julia V Busik
金额：
$ 38.02万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10440369
关键词：
Affect Animals Antibodies Apoptosis Apoptotic Binding Blood Vessels Bone Marrow Bone Marrow Transplantation Caliber Cell membrane Cells Ceramides Chimera organism Chronic Clinical Research Complication Complications of Diabetes Mellitus Cytokine Receptors Diabetes Mellitus Diabetic Retinopathy Disease Dyslipidemias Elements Endothelial Cells Endothelium Enzymes Functional disorder Generations Homing Hydrogen Bonding Hydrophobicity Hyperglycemia Immunotherapy Inflammation Inflammatory Injury Link Lipids Mammalian Cell Mediating Metabolic Modeling Molecular Outcome Pathogenesis Pathology Pathway interactions Patients Pharmacology Pharmacotherapy Process Proteins Retina Retinal Diseases Signal Transduction Site Sphingolipids Sphingomyelins Sphingosine Stress Surface Testing Therapeutic Vascular Diseases Wild Type Mouse acid sphingomyelinase bevacizumab cell injury cell type combat diabetic dihydroceramide improved improved outcome macular edema migration neovascular novel novel strategies prevent programs repaired retinal damage therapeutic evaluation therapeutically effective transmission process van der Waals force

项目摘要

Recent advances using pharmacotherapy greatly expand treatment options for diabetic retinopathy. Intravitreal anti-VEGF immunotherapy has proven to be effective in resolving both neovascular diabetic retinopathy (DR) and diabetic macular edema (DME). However, several large clinical studies reveal that about 40% of patients do not respond to anti-VEGF therapy. Moreover, anti- VEGF treatment is directed at the very late stage in the disease, when full reversal of retinal damage is difficult. Thus, finding novel strategies to cure this complication is paramount. The diabetic metabolic insult leading to retinal vascular degeneration involves initial endothelial cell damage due to low-grade chronic inflammation that is then inadequately repaired due to compromised availability and functionality of bone marrow derived circulating angiogenic cells (CACs). Normally migration to the site of endothelial injury and homing by CACs participates in the retinal vascular repair process. We previously demonstrated that bone marrow pathology with CAC dysfunction precedes and is necessary for retinal vascular degeneration in diabetes. The molecular metabolic link connecting both initial inflammation in the retina and dysfunctional CACs involves activation of acid sphingomyelinase (ASM), the central enzyme of sphingolipid signaling, converting sphingomyelin into pro-inflammatory and pro-apoptotic ceramide. Sphingomyelin is preferentially concentrated on the outer leaflet of the plasma membrane of all mammalian cells. Stress-induced ASM secretion leads to generation of ceramide therein. Once generated, ceramide, due to hydrophobic forces, hydrogen bonding and van der Waal forces, spontaneously coalesces into ceramide-rich platforms (0.5-5.0 mm diameter), macrodomains into which proteins insert and multimerize for the purpose of transmembrane signal transmission. The outcome of this process in retinal endothelial cells, is pro-inflammatory and apoptotic signaling. To intervene therapeutically in microvascular inflammation and apoptosis, our program developed a set of anti-ceramide antibodies. These antibodies are highly specific for ceramide and highly effective in binding monomeric ceramide generated on the surface of endothelial and other cells thereby preventing cytokine receptor clustering and pro-inflammatory and apoptotic signaling. The current application we will employ 6B5 anti-ceramide single chain variable fragment (scFv) to prevent endothelial cell activation and subsequent damage in the retina and to improve retinal vascular repair by correcting the function of bone marrow derived CACs.

使用药物治疗的最新进展极大地扩展了糖尿病治疗方案视网膜病。玻璃体内抗VEGF免疫疗法已被证明有效解决两者新生血管糖尿病性视网膜病（DR）和糖尿病黄斑水肿（DME）。但是，有几个大临床研究表明，大约40％的患者对抗VEGF治疗没有反应。此外，抗当完全逆转视网膜损伤时很难。因此，寻找治愈这种并发症的新型策略至关重要。导致视网膜血管变性的糖尿病代谢侮辱涉及初始内皮细胞损伤由于低度慢性炎症引起的，然后由于骨髓衍生的循环血管生成细胞（CACS）的可用性和功能受损。通常迁移到内皮损伤部位和CAC归巢的场所参与视网膜血管修复过程。我们先前证明了骨髓病理与CAC 功能障碍先于糖尿病的视网膜血管变性所必需。分子代谢环连接了视网膜和功能障碍CAC的初始炎症涉及酸鞘磷脂酶（ASM）的激活，鞘脂信号的中心酶，转化鞘磷脂成促炎和促凋亡神经酰胺。鞘磷脂优先集中在所有人的质膜的外叶上哺乳动物细胞。压力诱导的ASM分泌导致其中的神经酰胺产生。一次由于疏水力，氢键和范德华力而产生的神经酰胺，自发地合并为富含神经酰胺的平台（直径0.5-5.0毫米），大域中为了跨膜信号传输的目的，哪个蛋白质插入并进行了多重之中。这视网膜内皮细胞中此过程的结果是促炎和凋亡信号传导。到干预治疗微血管炎症和凋亡，我们的计划开发了一组抗神经酰胺抗体。这些抗体对神经酰胺高度特异，并且在结合在内皮和其他细胞表面产生的单体神经酰胺，从而防止细胞因子受体聚类以及促炎和凋亡信号传导。当前的应用程序我们将采用6B5抗陶瓷单链可变片段（SCFV）来防止内皮细胞激活和随后的视网膜损害，并通过校正视网膜血管修复来改善视网膜血管修复骨髓衍生的CAC的功能。