Synthetic Biology Based Polymerase and Promoter Engineering for Production of Next-Generation mRNA Therapeutics

当基于mRNA的生物制药成为全球新冠疫苗接种计划的支柱时，它们的治疗前景就实现了。除了疫苗，它们还可用于基因治疗，为治疗许多目前无法治愈的疾病提供了可能，包括癌症，神经系统疾病和心血管疾病。然而，关于mRNA制造系统的基本组成部分（RNA聚合酶和DNA模板）如何机械地相互作用以确定产品产量和质量仍然是未知的。这对于下一代mRNA治疗剂尤其如此，这些mRNA治疗剂比以前研究的mRNA产品大得多，也更复杂。这些产品通过以减少的剂量提供增强的治疗效果，提供了改善患者结局的潜力。然而，我们目前缺乏必要的工具来优化这些“难以生产”的分子的生产。在这个与阿斯利康的合作项目中，我们将使用合成生物学方法来设计新的生物成分，用于生产下一代mRNA治疗剂。这将包括核心合成生物学技术，如DNA序列设计，蛋白质的定向进化，生物系统的高通量筛选，生物分析和机器学习。

The therapeutic promise of mRNA-based biopharmaceuticals was realised when they formed the backbone of the world's vaccination programme against Covid-19. Beyond vaccines, they also have application in gene therapy, offering potential to treat many currently incurable conditions including cancer, neurological disorders and cardiovascular diseases. However, much is still unknown regarding how the fundamental components of mRNA manufacturing systems (the RNA Polymerase and DNA template) mechanistically interact to determine product yield and quality. This is particularly true for the next-generation of mRNA therapeutics that are substantially larger and more complex than previously studied mRNA products. These products offer potential to improve patient outcomes by delivering enhanced therapeutic efficacies at reduced doses. However, we currently lack the required tools to optimise manufacture of these 'difficult-to-produce' molecules.In this collaborative project with AstraZeneca, we will use a synthetic biology approach to design new biological components for production of next-generation mRNA therapeutics. This will include core synthetic biology techniques such as DNA sequence design, directed evolution of proteins, high-throughput screening of biological systems, bioanalytics, and machine learning.