Anti-ceramide immunotherapy for diabetic retinopathy

药物治疗的最新进展极大地扩大了糖尿病的治疗选择 视网膜病变。玻璃体内抗血管内皮生长因子免疫疗法已被证明在解决这两个问题上是有效的 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，几个大的 临床研究显示，约40%的患者对抗血管内皮生长因子治疗无效。此外，反- 血管内皮生长因子的治疗针对疾病的非常晚期，当视网膜损伤完全逆转时 是很困难的。因此，寻找新的策略来治愈这种并发症是至关重要的。 导致视网膜血管变性的糖尿病代谢损害涉及初始内皮细胞 由于轻度慢性炎症造成的细胞损伤，然后由于以下原因而无法得到充分修复 骨髓来源的循环血管生成细胞(CACs)的可用性和功能受损。 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 血管修复过程。我们之前用CAC证明了骨髓病理 功能障碍是糖尿病视网膜血管变性的先兆，也是必需的。分子 将视网膜的初始炎症和功能障碍的CACs连接起来的代谢环节包括 神经鞘磷脂信号转导的中心酶酸性鞘磷脂酶(ASM)的激活，转换 神经鞘磷脂转化为促炎和促凋亡神经酰胺。 鞘磷脂主要集中在细胞膜的外层小叶上。 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。一次 由于疏水作用力、氢键和范德华作用力而生成神经酰胺， 自发地结合成富含神经酰胺的平台(直径0.5-5.0 mm)，大范围区域形成 哪些蛋白质为了跨膜信号传递而插入和多聚体。这个 在视网膜内皮细胞中，这一过程的结果是促炎和凋亡信号。至 通过治疗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有很高的特异性，对 结合在内皮细胞和其他细胞表面产生的单体神经酰胺，从而防止 细胞因子受体聚集和促炎和凋亡信号。我们当前的应用程序 将使用6B5抗神经酰胺单链可变区(ScFv)来阻止内皮细胞 视网膜的激活和随后的损伤，并通过纠正视网膜血管修复 骨髓源性CACs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.