Development of a first-in-class, potent and safe, small synthetic anti-angiogenic peptide for treatment of retinopathy of prematurity

The long term objective of the proposed project is to develop a novel anti angiogenic therapy for retinopathy of prematurityROPa rare pediatric disease causing life long disabilityClinical significanceAdvances in neonatal care enable survival of many preterm newbornsbut these infants are plagued by increased incidence of retinopathy of prematuritywhich became a leading cause of childhood blindness worldwideROP radically diminishes quality of life of affected individuals and their familiesStandards of carelaseror cryotherapytreat pathological changesbut lead to other retinal damageThe main cause of ROP is overproduction of pro angiogenic vascular endothelial growth factorVEGFDespite promising early outcomeslong term clinical studies using VEGF antibody bevacizumab in ROP showed recurrent neovascularization leading to retinal detachmentwith prolonged lowering of VEGF levels in circulationSince VEGF is required for normal development of retina and other tissuesthere is an acute need for novel ROP drugs that suppress ocular angiogenesis without blocking VEGFThe objective of this proposal is to test the novel anti angiogenic agentPMDin a mouse model of ROPoxygen induced Ischemic retinopathyOIRPMDis aamino acid peptide based on Pigment Epithelium Derived FactorPEDFan endogenous anti angiogenic glycoprotein that maintains vascular balance in normal tissuesincluding the eyePMDis a potent anti angiogenic agentacting without VEGF blockadeAs a drug candidateit has several novel and unique featuresDrug like qualitiesPMDis the shortest peptide that still retains PEDF s anti angiogenic functionsPMDshows no toxicity against retinal cellsIt is retinoprotectiveSimilar to PEDFPEDF derived PMD peptides protect retinal pigment epithelium from oxidative stressand demonstrate anti fibrotic activityPMDdevelopment as a ROP drug candidate is de risked by its strong anti angiogenic activity in another neovascular eye disease modellaser induced choroidal neovascularizationCNVwithout adverse effectsIn Aimthe effective dose of PMDin mouse OIR will be determined and compared with the antibodies against mouse VEGFAFcommonly used as a positive control in OIRIt will be also testedwhether combining PMDwith AFcould produce additional benefits vs each single agentThe suppression of retinal and vitreal neovascularization will be used as primaryand fibrosis and inflammation as secondary readoutsIn Aimintravitreal PK and safety range of PMDwill be assessed in rabbitswith weightbehavior and general pathology as quantifiable safety read outsThe positive outcome of the proposed feasibility study will justify an investment into further drug development of PMDwith the ultimate goal of a novelpotent and safe drug that will become a major therapeutic advancepreventing disability in infants with ROP Retinopathy of prematurityROPis a disabling condition affecting low birth weight premature babiesand is the leading cause of blindness in childreneach yearnewborns in the US develop severe ROPcausing blindness ininfantsCurrent ROP therapies and drugs used to treat retinopathy in adults provide inadequate control of severe ROP and may cause additional vision impairmentsThe novel drug that treats ROP without serious side effects will improve the chances of preterm infants with ROP to retain their vision