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

• 批准号: 10200072
• 负责人: Julia V Busik
• 金额: $ 38.06万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200072
• 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

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.

药物疗法的最新进展极大地扩展了糖尿病的治疗选择 视网膜病变。玻璃体内抗 VEGF 免疫疗法已被证明可以有效解决这两个问题 新生血管性糖尿病视网膜病变（DR）和糖尿病性黄斑水肿（DME）。然而，几个大 临床研究表明，约 40% 的患者对抗 VEGF 治疗没有反应。此外，抗 VEGF 治疗针对疾病的最后阶段，此时视网膜损伤得到完全逆转 是困难的。因此，寻找治疗这种并发症的新策略至关重要。 导致视网膜血管变性的糖尿病代谢损伤涉及初始内皮细胞 低度慢性炎症造成的细胞损伤，然后由于以下原因无法充分修复 骨髓来源的循环血管生成细胞（CAC）的可用性和功能受损。 正常情况下，CAC 迁移至内皮损伤部位并归巢参与视网膜损伤 血管修复过程。我们之前证明了 CAC 的骨髓病理学 功能障碍先于糖尿病视网膜血管变性，并且是糖尿病视网膜血管变性所必需的。分子 连接视网膜初始炎症和功能失调的 CAC 的代谢联系涉及 激活酸性鞘磷脂酶 (ASM)，鞘脂信号传导的中心酶，将 鞘磷脂转化为促炎和促凋亡的神经酰胺。 鞘磷脂优先集中在所有质膜的外层 哺乳动物细胞。压力诱导的 ASM 分泌导致其中产生神经酰胺。一次 由于疏水力、氢键和范德华力而产生神经酰胺， 自发聚结成富含神经酰胺的平台（直径 0.5-5.0 毫米），大域形成 蛋白质插入并多聚化以实现跨膜信号传输。这 视网膜内皮细胞中这一过程的结果是促炎症和凋亡信号传导。到 治疗性干预微血管炎症和细胞凋亡，我们的项目开发了一套 抗神经酰胺抗体。这些抗体对神经酰胺具有高度特异性，并且非常有效 结合内皮细胞和其他细胞表面产生的单体神经酰胺，从而防止 细胞因子受体聚集以及促炎和凋亡信号传导。目前的应用我们 将采用6B5抗神经酰胺单链可变片段（scFv）来预防内皮细胞 视网膜的激活和随后的损伤，并通过纠正视网膜血管修复来改善视网膜血管修复 骨髓来源的 CAC 的功能。