Development of first-in-class TREM-1 inhibitors for neovascular retinal diseases

Project Summary Abstract Retinal neovascularizationRNVis a determinant cause of vision loss in retinopathy of prematurityROPdiabetic retinopathyDRand retinal vein occlusionRVOIn the USaboutof premature infants are affected by ROP annually and aboutmillion adults overyears have DRRVO is the second most common sight threatening retinal vascular disorder after DRComplications of conventional therapeutic options suggest an unmet need for new therapiesThe long term objective of this project is to develop a systemicnew mechanism basedefficient and low toxicity therapy for retinal neovascular diseasesTriggering receptor expressed on myeloid cellsTREMis upregulated under inflammatory conditions and is involved in the angiogenic signaling pathwayIn animal models of cancerwe found that blockade of TREMsuppresses macrophage infiltration into the tumor and improves survivalThe main hypothesis of this project is that blockade of TREMwill inhibit macrophage microglia infiltration into the retina and suppress RNVIn Phase I of the proposed projectwe will test this hypothesisCurrent TREMinhibitors all attempt to block binding of the unknown ligand to TREMand have a high risk of failure in clinical developmentThe blood retinal barrierBRBrepresents another challenge to the systemic treatment of retinopathySignaBlok developed a ligand independent TREMinhibitory peptide GFGFis well tolerated and can be formulated into SignaBlokandapos s retina permeable macrophagetargeted lipopeptide complexesLPCthat contain modified peptides of human apolipoprotein A I with epitopes for binding to scavenger receptorsCombination and exposure of these epitopes can be optimized to provide efficient and fast delivery of GFto the retina macrophages microgliaThis is anticipated to provide a prompt and effective therapeutic response during rapid RNV progressionPhase I specific aims are tooptimize GFLPC composition for fast and efficient delivery of GFto macrophages in vitrodetermine pharmacokineticsbioavailabilityand biodistribution of the most promising GFLPC formulations and select the optimal formulationandtest two doses of the optimal GFLPC formulation selected in Aimin the oxygen induced retinopathy mouse modelTreatment effects on vaso obliteration and pathological angiogenesis will be assessedHistological immunohistochemical analysis of intraretinal macrophage microglia infiltration and distribution of TREMand markers for activated macrophage microglial cellsIbaFin relation to the RNV will be also performedIt is anticipated that the Phase I study will identify novelfirst in class low toxic anti angiogenic TREMinhibitors and provide a powerful platform for development of effective and safe systemic therapies for neovascular retinal diseasesIf successfulPhase I will be followed in Phase II by toxicologyCMC ADME and pharmacology studiesfiling an IND application with the FDA and subsequent evaluation in humans Project Narrative Neovascular retinal diseases affected nearlymillion people in the U Sinand are the leading causes of vision loss and blindness in premature infants and in people overyears oldIntolerance or lack of response to conventional therapies as well as serious side effects indicate an unmet need for novel treatment optionsThe proposed research is anticipated to result in the development of novel mechanismbased systemic therapeutics that could substantially improve treatment of neovascular retinal diseases and decrease the nationandapos s annual cost of eye and vision disorders currently exceeding $billion