Anti-ceramide immunotherapy for diabetic retinopathy

University Of Oklahoma Hlth Sciences Ctr, Oklahoma City OK

Investigators

Linked publications & trials

Abstract

Evidence from large-scale clinical trials demonstrate strong association between lipid abnormalities and progression of diabetic retinopathy (DR), however the mechanism of dyslipidemia induced damage and the action of lipid targeting drugs in the retina are incompletely understood. Acid sphingomyelinase (ASM) is upregulated in diabetic retina and pharmacologic, siRNA, or microRNA inhibition of ASM prevented TNF-α and IL-1β-induced pro-inflammatory changes, barrier breakdown, cell death in retinal endothelial cells (RECs) and the development of DR. ASM activation results in hydrolysis of sphingomyelin in the outer leaflet of the plasma membrane to preferentially generate C16-ceramide and ceramide rich platform (CRP) formation. We identified C16:0/C26:0 ceramide imbalance with pathologic C16-ceramides increasing and retina-specific protective very- long chain C26-ceramides decreasing in the vitreous of patients with proliferative DR, similar to the C16:0/C24:0- ceramide ratio identified as a robust predictor of poor outcome from cardiovascular disease. DR is strongly associated with systemic inflammation; however, mechanisms responsible for circulating cells impacting the retina remain incompletely understood. Specifically, how diabetes impacts hematopoiesis and contribution of bone marrow cells to DR remains understudied. Generation of increased numbers of proinflammatory monocytes and neutrophils is known as myeloid skewing, which we have identified in both T1D and T2D. While another key hematopoietic population, termed myeloid angiogenic cells (MACs), is severely diminished in number and function in diabetic patients, including in individuals with DR, and contributes to inadequate vascular repair. Previously, we demonstrated ASM activation and increase in ceramide in both RECs and MACs in DR models. Critical to the function of MACs is their ability to egress from bone marrow (BM), enter the circulation and migrate to areas of injury. MAC mobilization and entry into tissues such as the retina critically depends on plasma membrane morphology and protein dynamics, which are mediated by membrane fluidity. Diabetes-induced changes in membrane lipid composition led to MACs remaining “trapped” within BM and incapable of mobilization into the circulation to mediate vascular repair . ASM inhibition corrected MAC release and normalized their function in rodent diabetes animal models and corrected retinal pathology. Importantly, human diabetic MACs, CD34+ cells, exhibit altered membrane fluidity and dynamics. To inhibit ASM-induced pathology, our program generated anti-ceramide antibody (Ab) to bind CRPs, preventing and mitigating ongoing apoptosis. Based on published and preliminary data, we hypothesize that predicting severity of DR in diabetic patients can be achieved by quantification of CRP formation in peripheral blood cells and that systemic administration of anti-ceramide Ab will restore physiological hematopoiesis eliminating myeloidosis and preserving MAC production/ function to prevent/reverse DR.