Developing Scg3 Raptamers as a novel targeted therapy for wet AMD

Age-related macular degeneration (AMD) is a prevalent degenerative condition affecting the macula, particularly among individuals over 65 years old, with its global burden expected to reach 288 million cases by 2040. Neovascular AMD, or wet AMD, represents the late stage of the disease, characterized by choroidal neovascularization (CNV), and accounts for around 1.25 million cases in the United States. Current treatment involves intravitreal injections targeting vascular endothelial growth factor (VEGF) to mitigate new blood vessel leakage and enhance visual clarity. However, these treatments only slow disease progression and come with various limitations, including resistance, inadequate responses in some patients, worsened vision despite treatment, and high costs. Additionally, approximately 40% of wet AMD patients either do not respond to or develop resistance to escalated anti-VEGF treatments. While gene therapy is being explored in clinical trials for these patients, it carries significant cost burdens. This underscores the urgent need for alternative therapies that provide novel therapeutic targets, enhanced efficacy, and a lower economic burden. We aim to create an aptamer-based therapy for wet AMD using modified ssDNA aptamers (known as Raptamers™) that specifically target Secretogranin III (Scg3), a newly identified angiogenesis and vascular leakage factor. Scg3 is notably expressed in the retinal ganglion cell layer and the retinal pigment epithelium (RPE), and its abundance is particularly pronounced in the vessels associated with choroidal neovascularization (CNV). Previous research has demonstrated effective reduction of CNV in mouse models of wet AMD and Retinopathy of Prematurity (ROP) with anti-Scg3 treatment. We have used our proprietary platform to develop high affinity Raptamers composed of a ssDNA oligo backbone with amino acid side modifications. We have developed Raptamers with high binding affinity to Scg3 and have examined their ability to neutralize Scg-3-mediated angiogenic effects in vitro and in vivo. Our objective is to develop a cost effective Raptamer-based therapeutic with a safety and efficacy profile superior to existing treatments for anti-VEGF unresponsive wet AMD patients. The project has two main objectives: 1) To develop high-affinity Raptamers against Scg3, enhance them with PEGs, and characterize their affinity by measuring their dissociation constant against Scg3, as well as evaluating their neutralizing effect using angiogenesis assays; 2) To assess the in vivo efficacy and safety of Scg3 Raptamers in a laser-induced CNV mouse model. Successfully completing these studies will demonstrate the effectiveness of a novel Scg3-Raptamer-based therapy for wet AMD and provide valuable insights for further research on its potential in treating retinopathy of prematurity.