RNA nanotechnology for rapid and sustainable preclinical iteration of gene therapeutics

虽然小分子和基于蛋白质的疗法的传统药物开发可能需要数年时间才能到达患者手中，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结果和降低成本。这种快速设计基因疗法的能力在新冠肺炎的爆发中得到了清楚的展示，当时几种领先的SARS-CoV-2疫苗候选药物正在利用基因疗法的一种形式--信使核糖核酸。然而，为了更好地应对新冠肺炎等迅速出现的病毒感染，并开发出更有针对性和个性化的癌症和遗传疾病治疗方法，需要一种更具适应性的基因治疗方法。目前提供基因治疗的方法包括接合、脂质纳米粒或病毒载体。然而，由于病变细胞的靶向性有限、毒性和/或制造过程漫长而昂贵，这些不同适应症的递送技术的开发一直受到阻碍。Six的专利可编程寡核苷酸递送系统(PODS)被设计为一种快速可扩展、无毒和有针对性的基因疗法递送方法。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。这项技术的独特之处在于，它允许基因疗法只需点击一下就可以实现快速迭代，并缩短从设计到制造的周期。该项目的**两个目标**是引入更快的迭代开发周期**，并引入从制造到测试的更**可持续的开发过程**。该项目中概述的创新方法寻求将准备时间从目前的24周减少到6周，这将使对新出现的传染病做出更快的反应，并同时开发多种疾病适应症的基因疗法。该项目将专注于以一种更环保的可持续方式来实现这一点。通过与在硅胶和活体服务领域领先的英国CRO公司Pharmidex合作，我们可以减少湿实验室工作，并通过使用他们的硅胶方法选择候选人和他们的级联方法将最佳候选人输送到疗效测试中，将动物的使用限制在仅基本的研究中。Six还将彻底改革制造工艺，减少试剂消耗和浪费，提高产量，并采用更高通量的方法进行体外测试，这将进一步减少塑料垃圾和动物衍生试剂的使用。该项目的成功将使药物输送系统开发时间增加6倍，通过在其工艺中引入更灵活的开发方法，并使Pharmidex能够开发更全面的体内实验服务套件，包括扩展到基于寡核苷酸的疗法。

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.