原子水平一体化构建腺相关病毒亲和层析介质及分子设计基础

基因治疗是21世纪以来人类攻破遗传性和获得性疾病最具革命性的医疗技术，近年来正在加速临床转化和商业发展。腺相关病毒AAV作为最具临床前景的基因载体之一，由于下游分离纯化产能不足而引发了药物成本高、民众可负担性差、临床及商业应用严重受限等一系列系统性问题。因此，本项目拟针对现有AAV下游纯化介质现状（多步层析活性损失高、蛋白配基使用成本高、配基无法实现原子水平真实环境下设计），提出一体化构建“AAV通用型仿生肽配基及高效化亲和介质”的设计理念，以核磁共振原子水平配基观测平台（具体包括WaterLOGSY, DEEP-STD NMR等技术）为核心手段来实现多肽配基在真实溶液环境中快速精准筛选，并通过引入聚合物刷手臂（解决多肽配基空间位阻缺陷）及反胶团溶胀法制备的超大孔微球骨架（解决病毒传统狭窄孔道传质受限），最终发展出具有高效、低成本、通用性的新一代AAV层析纯化材料。

Gene therapy is the most revolutionary medical technology for human to break through genetic and acquired diseases in 21st century. In recent years, Gene therapy is accelerating the clinical transformation and commercial development. Adeno-Associated Virus, AAV, as one of the most promising gene vectors, has a series of systemic problems, such as high cost of drugs, poor public affordability, and severe limitation in clinical and commercial applications, due to the lack of downstream purification capacity. Therefore, in view of the current situation of downstream purification media of AAV (high loss of multi-step chromatography activity, high cost of using protein ligands, and incapacity to design ligands at the atomic level and real environment), this project proposes the design concept, AAV universal bionic peptide ligands and high-efficiency affinity media. With the observation platform of nuclear magnetic resonance atomic level ligands (specifically including waterlogsy, DEEP-STD NMR and other technologies) as the core means, the project would achieve the rapid and accurate screening of peptide ligands in real solution environment. Furthermore, by introduction of polymer brush arm (to solve the steric hindrance defect of peptide ligands) and the super porous microsphere skeleton (to solve the restriction of traditional narrow channel mass transfer of virus), a new generation of AAV chromatography purification media would be constructed with high efficiency, low cost and versatility was finally developed Material.