SBIR Phase I: Optimizing Assembly of Bispecific Aptamer Therapeutics

这个小型企业创新研究(SBIR)第一阶段项目的更广泛影响/商业潜力是减少由视网膜疾病造成的可预防视力丧失的影响，例如湿性晚期黄斑变性(WAMD)和糖尿病黄斑水肿(DME)。视力丧失对经历失明的人的生活以及整个社会都有重大影响。视网膜治疗药物市场在2018年为130亿美元，预计2025年将增长到280亿美元。拟议的项目开发了一种新技术，以解决眼病的多个方面，预计将以更低的成本改善临床结果。这个小型企业创新研究(SBIR)第一阶段项目将确定结合抗VEGF和抗IL8适配子以产生双特异性适配子的最佳方法。将对两种不同的方法进行评估：1)直接化学合成法，其中单个适配子组分用于形成作为单一化合物合成的双功能适配子；2)杂交组装法，其中单个适配子组分单独合成，随后使用互补延伸用于组装。本项目将评估接头的同一性和长度对功能的影响，以及抑制活性，并将其与单个适配子成分的活性进行比较。性能最好的双特异性适配子将使用至少两种不同的聚乙二醇变异体进行聚乙二醇化，并进行进一步评估。将对聚乙二醇化化合物的生物物理性质进行评估。这些性质是确定双特异性适配子配方参数和预测玻璃体内半衰期的关键。表现最佳的聚乙二醇化双特异性适配子功能将在体内进行评估，以确认其在已建立的视网膜疾病动物模型中参与其目标的能力。该奖项反映了NSF的法定使命，并已通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project is to reduce the impact of preventable vision loss caused by retinal diseases such as the wet form of advanced macular degeneration (wAMD) and diabetic macular edema (DME). Vision loss has a significant impact on the lives of those who experience it as well as on society as a whole. The retinal therapeutics market was $13 B in 2018 and is projected to grow to $28B in 2025. The proposed project develops a new technology to address multiple aspects of eye disease, which is expected to improve clinical outcomes at reduced cost. This Small Business Innovation Research (SBIR) Phase I project will identify the best approach to combining anti-VEGF and anti-IL8 aptamers to generate a bispecific aptamer. Two different approaches will be evaluated: 1) direct chemical synthesis, in which the individual aptamer components are used to form a bispecific aptamer synthesized as a single compound, and 2) assembly by hybridization, in which individual aptamer components are synthesized separately with complementary extensions subsequently used for assembly. This project will assess the effect of linker identity and length on function, as well as the inhibitory activity, which will be compared with that of the individual aptamer components. The best performing bispecific aptamers will be PEGylated using at least two different PEG variants, and further evaluated. The biophysical properties of the PEGylated compounds will be assessed. These properties are key to establishing parameters for bispecific aptamer formulation and predicting intravitreal half-life. The best performing PEGylated bispecific aptamer function will be evaluated in vivo, to confirm its ability to engage its targets in an established animal model of retinal disease.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.