Developing multi-specific aptamers for safe, potent, and long-lasting treatment of geographic atrophy

项目摘要 地理萎缩（GA）是失明的主要原因，影响约150万美国人。目前没有治疗方法 因此，GA患者持续丧失视力，并且其中近一半是法定失明。 补体途径是免疫系统的一部分，并由眼睛中与年龄相关的病理变化激活。 广泛的遗传学研究、动物模型研究和临床观察已经确立了补体途径， 治疗GA最有希望的治疗靶点。两个后期抗补体项目都报告说 显著抑制GA进展，进一步证实了靶向补体的治疗潜力。然而，在这方面， 目前的方案存在持续时间短和安全性差的问题。因此，更安全、更持久的抗- 补充方案显然是必要的。 该SBIR项目的目的是开发一种基于多特异性适体的疗法，该疗法有可能克服 现有抗补体方案的局限性，并首次实现安全、有效和持久的GA治疗。 为此，Aptitude团队积累了丰富的适体发现经验。我们之前开发了 粒子展示方法显著提高了适体的性能。我们也取得了显著的成绩 初步研究证明构建多特异性适体的可行性。我们在适体发现方面的专长是 我们的合作者在GA临床前研究和临床试验方面的专业知识得到了补充。如果成功，该项目将 为GA患者带来高效和长效治疗的潜力。

PROJECT ABSTRACT Geographic atrophy (GA) is a leading cause of blindness, affecting ~1.5 million Americans. There is currently no treatment for GA; in consequence, GA patients continually lose vision, and nearly half of them are legally blind. The complement pathway is part of the immune system and is activated by age-related pathologic changes in the eye. Extensive genetics studies, animal model studies, and clinical observations have established the complement pathway as the most promising therapeutic target for treating GA. Two late-stage anti-complement programs have both reported significant inhibition of GA progression, further substantiating the therapeutic potential of targeting complements. However, the current programs suffer from short duration and poor safety profile. Therefore, a safer and longer-lasting anti- complement program is clearly needed. The purpose of this SBIR project is to develop a multi-specific aptamer-based therapeutics that has the potential to overcome the limitation of existing anti-complement programs, and achieve safe, potent, and durable GA treatment for the first time. To that end, the Aptitude team has accumulated extensive experience in aptamer discovery. We have previously developed the Particle Display method that significantly improves the aptamer performance. We have also performed significant preliminary studies to prove the feasibility of constructing multi-specific aptamers. Our expertise in aptamer discovery is complemented by our collaborators’ expertise in GA preclinical research and clinical trials. If successful, this project has the potential of bringing a highly efficacious and long-acting treatment to GA patients.