Anti-ceramide immunotherapy for diabetic retinopathy

药物治疗的最新进展大大扩展了糖尿病的治疗选择 视网膜病变玻璃体内抗VEGF免疫治疗已被证明是有效的解决这两个问题 新生血管性糖尿病视网膜病变（DR）和糖尿病黄斑水肿（DME）。然而，一些大型 临床研究表明，约40%的患者对抗VEGF治疗无反应。此外，反 VEGF治疗针对疾病的晚期阶段，此时视网膜损伤完全逆转 难以因此，找到治疗这种并发症的新策略至关重要。 糖尿病代谢损伤导致视网膜血管变性， 由于低度慢性炎症导致的细胞损伤，然后由于 骨髓来源的循环血管生成细胞（CAC）的可用性和功能性受损。 正常情况下，CACs向内皮损伤部位的迁移和归巢参与了视网膜神经元的凋亡。 血管修复过程我们以前证明了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 连接视网膜中初始炎症和功能障碍的CAC的代谢环节涉及 激活酸性鞘磷脂酶（ASM），鞘脂信号传导的中心酶， 鞘磷脂转化为促炎和促凋亡神经酰胺。 鞘磷脂优先集中在所有的细胞质膜的外小叶上， 哺乳动物细胞应激诱导的ASM分泌导致其中神经酰胺的产生。一旦 由于疏水力、氢键和货车范德华力， 自发聚结成富含神经酰胺的平台（0.5-5.0 mm直径）， 所述蛋白质插入并多聚化用于跨膜信号传递的目的。的 视网膜内皮细胞中该过程的结果是促炎和凋亡信号传导。到 在微血管炎症和细胞凋亡的治疗干预，我们的计划开发了一套 抗神经酰胺抗体。这些抗体对神经酰胺具有高度特异性，并且在治疗中高度有效。 结合内皮细胞和其他细胞表面上产生的单体神经酰胺， 细胞因子受体聚集以及促炎和凋亡信号传导。当前的应用程序我们 将采用6 B5抗神经酰胺单链可变片段（scFv）， 激活和随后的视网膜损伤，并通过纠正视网膜血管损伤改善视网膜血管修复。 骨髓源性CAC的功能。

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.