Research Project
9553098
Project Summary/Abstract Retinal neovascularization (RNV) is a determinant cause of vision loss in retinopathy of prematurity (ROP), diabetic retinopathy (DR) and retinal vein occlusion (RVO). In the US, about 16,000 of premature infants are affected by ROP annually and about 4.1 million adults over 40 years have DR. RVO is the second most common sight-threatening retinal vascular disorder after DR. Complications of conventional therapeutic options suggest an unmet need for new therapies. The long-term objective of this project is to develop a systemic, new mechanism-based, efficient and low-toxicity therapy for retinal neovascular diseases. Triggering receptor expressed on myeloid cells (TREM-1) is upregulated under inflammatory conditions and is involved in the angiogenic signaling pathway. In animal models of cancer, we found that blockade of TREM-1 suppresses macrophage infiltration into the tumor and improves survival. The main hypothesis of this project is that blockade of TREM-1 will inhibit macrophage/microglia infiltration into the retina and suppress RNV. In Phase I of the proposed project, we will test this hypothesis. Current TREM-1 inhibitors all attempt to block binding of the unknown ligand to TREM-1 and have a high risk of failure in clinical development. The blood-retinal barrier (BRB) represents another challenge to the systemic treatment of retinopathy. SignaBlok developed a ligand-independent TREM-1 inhibitory peptide GF9. GF9 is well-tolerated and can be formulated into SignaBlok's retina-permeable macrophage- targeted lipopeptide complexes (LPC) that contain modified peptides of human apolipoprotein A-I with epitopes for binding to scavenger receptors. Combination and exposure of these epitopes can be optimized to provide efficient and fast delivery of GF9 to the retina macrophages/microglia. This is anticipated to provide a prompt and effective therapeutic response during rapid RNV progression. Phase I specific aims are to: 1) optimize GF9-LPC composition for fast and efficient delivery of GF9 to macrophages in vitro, 2) determine pharmacokinetics, bioavailability, and biodistribution of the most promising GF9-LPC formulations and select the optimal formulation, and 3) test two doses of the optimal GF9-LPC formulation selected in Aim 2 in the oxygen-induced retinopathy mouse model. Treatment effects on vaso-obliteration and pathological angiogenesis will be assessed. Histological/immunohistochemical analysis of intraretinal macrophage/microglia infiltration and distribution of TREM-1 and markers for activated macrophage/microglial cells (Iba-1, F4/80) in relation to the RNV will be also performed. It is anticipated that the Phase I study will identify novel, first-in-class low-toxic anti-angiogenic TREM-1 inhibitors and provide a powerful platform for development of effective and safe systemic therapies for neovascular retinal diseases. If successful, Phase I will be followed in Phase II by toxicology, CMC,ADME and pharmacology studies, filing an IND application with the FDA and subsequent evaluation in humans.
