RNA nanotechnology for rapid and sustainable preclinical iteration of gene therapeutics

虽然传统的小分子和蛋白质疗法的药物开发可能需要数年时间才能到达患者，但基于基因疗法的更灵活的多学科方法不仅有可能缩短上市时间，而且还可以改善治疗效果并降低成本。这种快速设计基因疗法的能力在COVID-19爆发期间得到了清楚的证明，其中几种领先的SARS-CoV-2候选疫苗正在利用mRNA，这是一种基因疗法。然而，为了更好地应对快速出现的病毒感染，如COVID-19，并开发更具针对性和个性化的方法来治疗癌症和遗传性疾病，需要一种更具适应性的方法来提供基因疗法。目前用于递送基因疗法的方法包括缀合、脂质纳米颗粒或病毒载体。然而，这些用于不同适应症的递送技术的开发受到病变细胞的有限靶向特异性、毒性和/或冗长且昂贵的制造过程的阻碍。Sixfold的专利可编程寡核苷酸递送系统（PODS）已被设计为一种快速可扩展、无毒和靶向的基因治疗递送方法。该技术已在体外和体内哺乳动物系统中得到验证，显示出良好的安全性和生物分布。该技术的独特之处在于，它允许基因疗法简单地“点击”到他们的PODS上，从而实现快速迭代和短的设计到制造的交付周期。该项目的两个目标是引入一个更快速的开发周期，以实现快速迭代，并引入一个从制造到测试的可持续发展过程。该项目中概述的创新方法旨在将交货时间从目前的24周缩短至6周，这将允许对新出现的传染病做出更快速的反应，并在多种疾病适应症中并行开发基因疗法。该项目将侧重于以环境上更可持续的方式做到这一点。通过与Pharmidex（一家提供计算机模拟和体内服务的领先英国CRO）合作，我们可以减少我们的湿实验室工作，并通过使用其计算机模拟方法进行候选人选择和级联方法将最佳候选人用于功效测试，将动物的使用限制在必要的研究中。Sixfold还将彻底改革生产工艺，减少试剂消耗和浪费，提高产量，以及采用更高通量的体外测试方法，这将进一步减少塑料废物和动物的使用，该项目的成功将使Sixfold成为药物输送系统开发时代的世界领导者，通过将更敏捷的开发方法引入其过程，允许Pharmidex开发更全面的体内实验服务套件，包括扩展到基于阿托伐他汀的治疗。

While traditional pharmaceutical development of small-molecule and protein-based therapeutics can take years to reach patients, a more agile multi-disciplinary approach based on gene therapies has the potential to not only reduce time to market, but also improve therapeutic outcomes and reduce cost. This ability to rapidly engineer gene therapies has been clearly demonstrated during the outbreak of COVID-19, whereby several of the leading SARS-CoV-2 vaccine candidates are utilising mRNA, a form of gene therapy. However, in order to better respond to rapidly emerging viral infections such as COVID-19 and develop more targeted and personalised approaches for the treatment of cancer and genetic disorders, there is a need for a more adaptable approach to the delivery of gene therapies. Current approaches for the delivery of gene therapies, include conjugation, lipid nanoparticles or viral vectors. However, the exploitation of these delivery technologies for diverse indications has been impeded by the limited targeting specificity of diseased cells, toxicity and/or the lengthy and expensive manufacturing process. Sixfold's patented Programmable Oligonucleotide Delivery System (PODS) has been engineered as a rapidly scalable, non-toxic and targeted approach for the delivery of gene therapies. The technology has been validated in vitro and in vivo mammalian systems, showing favourable safety and biodistribution. The technology is unique in that it allows gene therapies to be simply 'clicked' onto their PODS enabling rapid iteration and short design-to-manufacture lead times.The **two objectives** of this project are to introduce a more **rapid development cycle** for fast iteration and introduce a significantly more **sustainable development process from manufacturing through to testing**. The innovative approach outlined in this project seeks to reduce the lead times from the current 24 weeks to 6 weeks, which will allow for a more rapid response to emerging infectious diseases AND the parallel development of gene therapeutics across multiple disease indications. This project will focus on doing this in a more environmentally sustainable way. By partnering with Pharmidex, a leading UK CRO offering in silico and in vivo services, we can reduce our wet lab work and limit the use of animals to only essential studies by using their in silico methodologies for candidate selection and their cascade approach to funnel the best candidates into efficacy testing. Sixfold will also overhaul the manufacturing process reducing reagent consumption and waste, and increasing yield, as well as taking on a more high-throughput approach to in vitro testing which will further reduce plastic waste and the use of animal-derived reagents.The success of this project will make Sixfold world leaders in drug delivery system development times through the introduction of a more agile development methodology into their process and allow Pharmidex to develop a more comprehensive suite of in vivo experimentation services including an expansion into oligonucleotide-based therapeutics.