Sunday, April 28, 2024
4/28/2024
PROJECT SUMMARY Choroidal neovascularization (CNV), the wet type of age-related macular degeneration (AMD), is a major cause of blindness in the elderly. Current anti-vascular endothelial growth factor (VEGF) therapy has a number of serious limitations including: 1) many patients respond poorly or not at all to mono anti-VEGF treatments (non-responders); 2) the long-term outcomes are suboptimal even for responders and can lead to anti-VEGF resistance; 3) repetitive intravitreal injections adversely affect quality of life and increase the risk of local complications. Therefore, alternative or combination therapies to improve CNV treatment efficacy represent a major unmet clinical need. Anti-VEGF resistance in CNV patients is frequently associated with arteriolar CNV (large-caliber branching arterioles, vascular loops and anastomotic connections), in which macrophages are known to play important roles, whereas anti-VEGF responders are characterized by capillary CNV, in which VEGFR2 signaling has an overriding role. The secretory apolipoprotein A-I (apoA-I) binding protein (AIBP) binds to its partner apoA-I or high-density lipoprotein (HDL) to enhance cholesterol efflux and inhibit lipid raft- anchored VEGFR2 signaling in hyperactive endothelial cells. By binding the toll-like receptor 4 (TLR4), AIBP augments cholesterol efflux from macrophages, thereby suppressing inflammation (Fig. 1). VEGF is an inflammatory cytokine that recruits macrophages to vascular sites of inflammation where heightened secretion of additional VEGF and other pro-angiogenic factors by macrophages creates positive feedback loops. We hypothesize that combinations of AIBP, apoA-I and anti-VEGF will combat anti-VEGF resistance by simultaneously targeting VEGF, endothelial cells, and macrophages. We recently showed that this combination therapy was effective in treating anti-VEGF resistance by potently inhibiting arteriolar CNV, whereas aflibercept monotherapy was ineffective (IOVS, 2022). Our objective is to develop AIBP/apoA-I/anti-VEGF combination gene therapy with broad application and long-term efficacy for AMD, thereby obviating the limitations of current Aim1 will determine the role of AIBP in pathological angiogenesis. Aim 2 will test the hypothesis that targeting macrophages with AIBP is necessary to overcome anti-VEGF resistance in CNV by combination therapy. Aim 3 will develop long-term AIBP/apoA-I/anti-VEGF combination gene therapy for CNV in mouse AMD models.
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