Mechanistic study and therapeutic application of AIBP in AMD

项目总结 脉络膜新生血管(CNV)，湿性老年性黄斑变性(AMD)，是一种主要的 导致老年人失明的原因。目前的抗血管内皮细胞生长因子(VEGF)疗法有许多 严重的局限性包括：1)许多患者对单一抗血管内皮生长因子治疗的反应很差或根本没有反应 (无应答者)；2)即使对应答者来说，长期结果也是次优的，并可能导致抗血管内皮生长因子 阻力；3)反复玻璃体内注射对生活质量产生不利影响，并增加局部风险 并发症。因此，提高CNV治疗疗效的替代疗法或联合疗法代表着一种 尚未满足的主要临床需求。新生血管患者的抗血管内皮生长因子抵抗常与小动脉新生血管相关 (大口径分支小动脉、血管环和吻合口连接)，其中巨噬细胞 已知发挥重要作用，而抗血管内皮生长因子应答者以毛细血管新生血管为特征，其中 VEGFR2信号具有压倒一切的作用。分泌型载脂蛋白A-I结合蛋白(AIBP) 与其伙伴apoA-I或高密度脂蛋白(HDL)结合，以促进胆固醇外流和抑制脂筏- 在过度活跃的内皮细胞中锚定VEGFR2信号。通过结合Toll样受体4，AIBP 增加巨噬细胞的胆固醇流出，从而抑制炎症(图1)。血管内皮生长因子是一个 炎性细胞因子，将巨噬细胞招募到炎症的血管部位，在那里分泌增加 巨噬细胞产生额外的血管内皮生长因子和其他促血管生成因子，形成正反馈循环。我们 假设AIBP、apoA-I和抗血管内皮生长因子抗体的组合将通过 同时靶向血管内皮生长因子、内皮细胞和巨噬细胞。我们最近证明了这种组合 治疗通过有效地抑制微动脉CNV而有效地治疗抗血管内皮生长因子抵抗，而阿普利赛特 单一疗法无效(IOVS，2022)。我们的目标是开发AIBP/apoA-I/抗-VEGF组合 基因治疗AMD具有广泛的应用性和远期疗效，从而消除了目前的局限性 AIM1将决定AIBP在病理性血管生成中的作用。目标2将测试目标定位的假设 合并AIBP的巨噬细胞是克服CNV抗血管内皮生长因子耐药所必需的。目标 3将开展AIBP/apoA-I/抗-VEGF联合基因治疗AMD小鼠模型CNV的长期研究。

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.