Multi-Modal Mechanisms of Novel Sulfated Non Anticoagulant Heparin inSickle Cell Disease Management

AbstractThe pathogenesis of Sickle cell diseaseSCDcomprises a complex interplay of factors associated with vascular endothelial activationintense inflammationand increased sickle cell adhesionMicrovascular occlusion in SCD is initiated by adhesion of sickle red blood cellsRBCsto the endotheliumleading to acute painful vasoocclusive crisisVOCand the clinical morbidity in SCDTreatment strategies include the use of chronic blood transfusionhydroxyureaand bone marrow transplantation but these treatments are not without significant side effectsBecause of the inherent complexity of this diseaseit is unlikely that a single therapeutic strategy will be beneficialIn this Phase I Application we propose to study a sulfated oxidized non anticoagulant low molecular weight heparinLMWHreferred to as S NACHwith an extensive range of bioactivities that constitute a multi modal approach to management of SCDOf significant importance to the development of this agent is the fact that S NACH exerts these activities without causing hemostaticbleedingside effects that are associated with the clinical use of LMWHsAdditionallyS NACH has been optimized to directly interact with hemoglobin to exert desirable therapeutic benefitsLMWHs have been tested for clinical management of VOC in SCDand we have previously shown that LMWH tinzaparin significantly shortened both duration of VOC crisis and hospitalization byand resulted in significant and more rapid reduction of painHoweverdespite the demonstrated potential benefits of LMWHs for SCDsafety concerns associated with the narrow therapeutic indexbleeding risksare a major barrier to dose escalation optimization of treatmentsConsequentlyfurther studies are clearly warrantedOur novel multi modal compound S NACH provides the opportunity to pursue studies that will conclusively establish safety and efficacyIn this proposalwe will perform proof of concept in vitro and in vivo pre clinical studieswhich would expand on our rich body of pilot data and establish efficacy in a mouse model of SCDand lay critical foundation for the potential advancement of this agent to clinical applicationsUpon successful completionwe willin Phase II studiesrigorously explore various formulations of S NACHincluding oral nanoformulationsgeared towards feasible administration in acute and chronic situationsconduct GLP scale upconduct x ray crystallography studies to ascertain the detailed nature of interactions of S NACH with Hband utilize gained knowledge to further optimize design and synthesis for efficacy and specificityconduct safety and efficacy studies in preclinical models for the advancement for acute and chronic disease management in SCD patients NARRATIVE The pathogenesis of Sickle cell diseaseSCDis a complex interplay of multiple factors associated with vascular endothelial activationintense inflammationand increased sickle cell adhesion driven by the sickling of red blood cells in SCDTreatment with low molecular weight heparinLMWHhas shown clinical efficacy in decreasing the length of hospitalization and pain scoresbut bleeding side effects limit the use of these LMWHsIn this proposalwe will test a novel Oxidized sulfated oxidized non anticoagulant LMWH called S NACHwhich is devoid of systemic anticoagulation activities but possess potent anti sicklingantiselectinanti inflammatoryand antithrombotic activities without affecting hemostasis