Quality, yield and cost optimisations of in vitro transcription reactions for saRNA therapeutics

核酸作为疫苗和治疗手段的潜力才刚刚被认识到，新冠病毒mRNA疫苗的成功在一定程度上要归功于扩大规模和生产的速度。VaxEquity是一家寻求开发新型第二代RNA疫苗和疗法的生物技术公司。该项目与工艺创新中心合作，将提高第二代RNA疫苗和基于自我扩增RNA的疗法，特别是多价saRNA流感疫苗的生产过程的效率。该项目将通过实验确定和定义关键质量属性（cqa），即saRNA的关键属性和影响这些cqa的制造变量，这些cqa用于RNA转录过程（从更稳定的DNA模板中产生活性RNA分子）。盖上RNA以增强稳定性、加工和翻译的过程将与制造过程一起进行评估，并在初级saRNA合成完成后作为单独的反应进行评估。研究将在小型实验室规模上进行，以确定优化条件和对这些条件产生严重影响的因素。将对优化条件进行测试，以确定随后生产广效saRNA流感疫苗的可扩展性，从而进入临床前和临床开发阶段。制造基于核酸的药物是昂贵的，通过优化saRNA的条件，与mRNA相比，saRNA有可能将剂量减少10倍，可以实现原材料和未来剂量需求规模的显著节省。该项目的好处在于，英国领先的独立技术创新中心（拥有复杂核酸疗法有效创新的合适专家和实践能力）与英国RNA疫苗和治疗生物技术公司VaxEquity合作，确定、建立和保护saRNA制造的优化过程。

The potential of nucleic acids as vaccines and therapeutics is only just being realised and the success of the Covid mRNA vaccines is due in part to the rate at which scale-up and manufacture was possible. VaxEquity is a biotechnology company seeking to develop novel, second-generation RNA based vaccines and therapeutics. Working in collaboration with the Centre for Process Innovation, this project will drive efficiencies in the manufacturing process for second generation RNA vaccines and therapeutics based on self-amplifying RNA and, specifically, for amulti-valent saRNA flu vaccine. The project will identify and define experimentally the Critical Quality Attributes (CQAs) i.e. the key properties for saRNA and the manufacturing variables that impact these CQAs for the process of RNA transcription (the creation of active RNA molecules from the more stable DNA template) in batch and fed batch processes. The process of capping the RNA to enhance stability, processing and translation will be evaluated in tandem with the manufacturing process and as a separate reaction after the primary saRNA synthesis is complete. Studies will be run at small, laboratory scale to identify the optimised conditions and the factors that critically impinge on these conditions. Optimised conditions will be tested to establish scalability for the subsequent manufacturing of a broad-acting saRNA influenza vaccine to proceed into preclinical and clinical development. Manufacturing nucleic acid-based medicines is expensive and through the optimisation of conditions for saRNA, which has the potential to reduce dose compared to mRNA by \>10-fold, significant savings from both raw materials and the size of future dose requirements can be achieved.The benefits of the project for the UK will be to identify, establish and protect an optimised process for saRNA manufacture in a partnership between the UK's leading independent technology innovation centre that has the right experts and practical capabilities for effective innovation of complex nucleic acid therapies and UK-based RNA vaccine and therapeutics biotechnology company VaxEquity.