Targeting SDF-1 for effective wet AMD treatment

项目摘要 湿性黄斑变性（AMD）是导致以下人群新失明的主要原因： 55岁或以上目前治疗湿性AMD的标准是抗血管内皮生长因子（VEGF） 药物，如Lucentis、Eylea和Avastin（标签外使用）。这些抗VEGF剂抑制VEGF介导的 血管生成，并有效阻止甚至逆转大多数患者的视力丧失。尽管是最好的 目前可用的治疗，它有两个关键的缺点：1）有限的近期视力增益和差的长期， 长期视力维持;（2）主要费用和治疗负担。首先，尽管继续治疗，只有约1/3的 患者在前12个月内获得>3线视力; 3-4年后，大多数患者开始失明 再次，并最终降至治疗前水平。其次，患者必须每隔1至2天返回诊所 玻璃体内注射-一个专门的，不舒服的和昂贵的程序，代表了显着的 治疗负担。 该SBIR的目的是开发针对SDF-1的高度稳定的适体，其可用作 湿性AMD的正交治疗。SDF-1长期以来被认为在脉络膜细胞凋亡中起重要作用。 新生血管形成（CNV）是湿性AMD的标志性病理过程。Aptitude团队已经积累了 丰富的适体发现经验。我们以前开发了粒子显示方法， 显著提高了适体的性能。此外，我们还进一步改进了直接 筛选完全修饰的适体，其能够实现更长的功效持续时间。我们在适体发现方面的专业知识 与我们合作者在湿性AMD临床前研究方面的专业知识相辅相成。我们的合作者是 第一个证明SDF-1在CNV中的作用，并拥有相关动物模型的深入专业知识。如果 成功，该项目有可能带来更有效和负担得起的治疗湿性AMD 患者

PROJECT ABSTRACT Wet Age-related Macular Degeneration (AMD) is the leading cause of new blindness among people who are 55 or older. The current standard of care for wet AMD is anti-Vascular Endothelial Growth Factor (VEGF) agents, such as Lucentis, Eylea, and Avastin (used off-label). These anti-VEGF agents inhibit VEGF-mediated angiogenesis, and effectively stop or even reverse the vision loss for most patients. Despite being the best treatment currently available, it has two critical shortcomings: 1) limited near-term vision gain and poor long- term vision maintenance; (2) major cost and treatment burden. First, despite continued treatment, only ~1/3 of the patient gain >3 lines of vision over the first 12 months; after 3-4 years, most patients start losing vision again and eventually dropping to pre-treatment levels. Second, patients must return to the clinic every 1 to 2 months for intravitreal injections – a specialized, uncomfortable and costly procedure that represents significant treatment burden. The purpose of this SBIR is to develop highly stable aptamers against SDF-1, which may serve as an orthogonal treatment for wet AMD. SDF-1 has long been known to play an important role in choroidal neovascularization (CNV), the landmark pathological process of wet AMD. The Aptitude team has accumulated extensive experience in aptamer discovery. We have previously developed the Particle Display method that significantly improves the aptamer performance. Moreover, we have made further improvement to directly screen for fully modified aptamers that enables longer duration of efficacy. Our expertise in aptamer discovery is complemented by our collaborators’ expertise in wet AMD preclinical research. Our collaborator is among the first to demonstrate the role of SDF-1 in CNV, and possess in-depth expertise in relevant animal models. If successful, this project has the potential of bringing more efficacious and affordable treatment to wet AMD patients.