Artificial intelligence driven platform to aid experimental design of optimised plasmid DNA for in vivo expression of biologics

基于DNA的治疗分子的体内表达是一种新兴的平台，旨在通过施用病毒或非病毒DNA将生物化合物递送至患者。现在已知质粒DNA中特定序列（如十字形、发夹、回文、微小RNA靶、隐蔽剪接位点）的存在可对DNA的结构具有强烈影响，可影响所产生的DNA的质量和表达元件的性能。此外，在特定DNA元件的存在与对结构、表达水平、免疫刺激作用和质粒产生的下游效应之间存在复杂的关系。人工智能驱动的生物信息学可以帮助开发用于自动分析DNA元件的新型计算工具，并与文献相结合，用于指导优化质粒系统的设计。合成生物学可以提供一种表征新设计及其输出的途径，用于将结构考虑纳入基于核酸的疗法。在这个项目中，我们将通过采用迭代实验和计算方法以及利用先进的机器学习算法来优化基于质粒的治疗设计。遵循这种系统化设计方法，我们的目标是了解如何在体外和可能的体内研究中成功地转移工业相关的治疗系统设计。了解如何将基序设计规则转化为哺乳动物细胞系和体内系统将是一项重大成就，使我们能够在未来彻底改变治疗生产。

DNA-based in vivo expression of therapeutic molecules is an emerging platform aiming to deliver biologic compounds to the patient via administration of viral or non-viral DNA. It is now known that the presence of particular sequences (such as cruciform, hairpins, palindromes, micro-RNA targets, cryptic splice sites) within the plasmid DNA can have a strong impact on the structure of the DNA, can affect the quality of the DNA produced, and the performance of expression elements. Additionally, there is a complex relationship between the presence of particular DNA elements and downstream effects on structure, expression levels, immunostimulatory effects and plasmid production. Artificial intelligence-driven bioinformatics can aid the development of novel computation tools for the automated analysis of DNA elements and, combined with literature, used to guide the design of optimised plasmid systems. Synthetic biology can offer a route for characterisation of novel designs and their output for incorporation of structure considerations into nucleic acid-based therapeutics. In this project we will optimise plasmid-based therapeutic design by adopting iterative experimental and computational approaches in addition to leveraging advanced machine learning algorithms. Following this systematic design approach our aim is to understand how to successfully transfer industrially-relevant therapeutic systems design within in vitro and, possibly, in vivo studies. Achieving an understanding of how to translate motif design rules into mammalian cell lines and in vivo systems will be a major achievement enabling us to revolutionise therapeutic production in the future.