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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.

药物治疗的最新进展极大地扩展了糖尿病的治疗选择