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

基于DNA的治疗分子体内表达是一种新兴的平台，旨在通过给药病毒或非病毒DNA将生物化合物传递给患者。现已知道，质粒DNA中存在的特定序列(如十字形、发夹、回文、微型RNA靶标、隐蔽剪接位点)可以对DNA的结构产生强烈的影响，可以影响DNA生产的质量和表达元件的性能。此外，特定DNA元件的存在与下游对结构、表达水平、免疫刺激效应和质粒生产的影响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DNA成分自动分析的新计算工具，并结合文献用于指导优化的质粒系统的设计。合成生物学可以为表征新的设计及其成果提供一条途径，以便将结构考虑纳入基于核酸的疗法中。在这个项目中，除了利用先进的机器学习算法外，我们还将通过采用迭代实验和计算方法来优化基于质粒的治疗设计。遵循这一系统设计方法，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与工业相关的治疗系统设计。理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.