年龄相关性黄斑变性的原发病变和继发致盲的发病机制和干预新策略

Age-related macular degeneration (AMD) progressively impairs central retina, and therefore is currently the leading cause of visual impairment among elderly people. While degeneration of retinal pigment epithelium (RPE) is demonstrated as the primary trigger for AMD, choroidal neovascularization (CNV) secondary to RPE degeneration is the most often cause for severe vision loss among AMD patients eventually. To date, the pathogenic mechanisms by which initiate RPE degeneration and following CNV progression have not been fully illustrated in AMD. No effective treatment has been developed to prevent RPE degeneration in the disease. Antibodies against vascular endothelial growth factor (VEGF) have been demonstrated to be effective in the treatment of CNV in the clinic, but have also been challenged by substantial difficulties such as the large average number of injections, the unaffordable cost and the high rate of reoccurrence of CNV. Here, we firstly proposed to investigate the critical roles of mTOR signaling pathway and its relevant competing endogenous RNA (ceRNA) in RPE degeneration and CNV formation. Secondly, we would test a number of therapeutic strategies for AMD including an approach of genetically silencing VEGFA in the targeted cells by employing the combination of AAV-delivered system and CRISPER/Cas9 editing technique, and multiple approaches of targeting mTOR pathway and its relevant ceRNA in retinale. Altogether, this study is aimed to illustrate the fundamental theories underlying RPE degeneration and CNV progression in AMD, and to discover new safe and efficient therapeutic strategies for AMD.

年龄相关性黄斑变性（AMD）进行性损害中央视网膜，是老年人群不可逆视力损伤的首要病因。视网膜色素上皮细胞（RPE）变性是AMD的原发病变，继发感光细胞丢失是AMD视觉损害的起因，脉络膜新生血管（CNV）的形成是AMD最终致盲的首要原因。迄今，RPE变性和CNV形成的机制尚未完全清楚，临床尚缺乏针对RPE原发变性的有效干预措施。抗血管内皮因子（VEGF）抗体药物虽能显著抑制CNV，但依然面临治疗次数多、经济负担重和复发率高等困难。本项目拟首先研究在RPE细胞变性和CNV形成中，mTOR信号通路及其相关的竞争性内源RNA（ceRNA）的关键致病机制；其次探索腺相关病毒介导结合CRISPER/Cas9基因编辑技术靶向敲除VEGFA和多手段干预mTOR信号及相关的ceRNA等策略在治疗AMD中的有效性和安全性。本研究旨在揭示AMD病程的核心机制，找到靶向修复AMD相关视网膜损伤的新干预策略。

年龄相关性黄斑变性（AMD）进行性损害中央视网膜，是老年人群不可逆视力损伤的首要病因。视网膜色素上皮细胞（RPE）变性是AMD的原发病变，继发感光细胞丢失是AMD视觉损害的起因，脉络膜新生血管（CNV）的形成是AMD最终致盲的首要原因。迄今，RPE变性和CNV形成的机制尚未完全清楚，临床尚缺乏针对RPE原发变性的有效干预措施。抗血管内皮因子（VEGF）抗体药物虽能显著抑制CNV，但依然面临治疗次数多、经济负担重和复发率高等困难。本研究1）发现AMD原发病变的关键特征、核心机制、调控网络及关键干预靶点；2）构建全新递送系统，为眼底新生血管的基因治疗提供新策略；3）发现了VEGFB对视网膜神经元的保护机制以及临床上抗VEGF抗体干预VEGFB的风险；4）系统揭示了环状RNA调控眼底新生血管的分子机制，揭示了临床上部分患者对抗VEGF抗体治疗无效的重要机制。本研究成果为AMD的精准分子诊断、靶向药物治疗和有效预后评估提供理论基础和干预靶点。