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.