Combinatorial genome editing to create enhanced biomanufacturing platforms

该项目将加强创新药物的生产，提供更可预测的成功途径，并在增加确定性的情况下，使能够更迅速、更廉价地生产改变生活的药物，从而对患者和经济产生宝贵的影响。重点是改进用于根据天然分子和蛋白质知识制造药物的系统，这些知识是治疗其他无法治愈的疾病的有效药物。这些分子通常被称为生物制药（或生物治疗药物或生物制剂），以胰岛素为代表，胰岛素是一种由胰腺细胞中的遗传密码连接成特定顺序的较小成分（氨基酸）的聚合物。胰岛素在糖尿病治疗中改变生活的后果是普遍理解的，但它所呈现的只是许多生物制药中的一种，这些生物制药已经或正在或将用于治疗癌症（如阿瓦斯汀）、凝血障碍（如Factor VIII）或类风湿性关节炎（如Remicade）等疾病。这些药物中的每一种都是通过基因工程制成的，它们是由哺乳动物细胞在发酵罐中合成的。具有如此巨大潜力的药物的研究和安全性验证是漫长而昂贵的，但对患者、社会和经济来说，回报是巨大的。生物制药在制药市场占据主导地位，2013年，十大畅销药物中有7种是生物制药，总销售额为580亿美元。潜在的回报是巨大的，但同样巨大的投资，因此病人和卫生机构的成本很高。人们希望使进入市场的途径更容易，更不容易失败，从而降低制造成本，从而降低治疗成本。这种情况由于新型生物药物的发展而变得更加复杂——这些分子被设计得更有针对性、更有选择性。治疗至今无法治愈的疾病。许多这样的生物制药可以设计（用于“理论”制造），但不能用目前工业使用的细胞生产（或生产不良）。这提出了当前项目需要解决的挑战——制造一种用于制造大多数新兴生物制药的新版本的细胞。这种方法新颖、令人兴奋，并有可能改变生物制药商业生产的可能性。我们将设计成一个新的制造平台的细胞是中国仓鼠卵巢（CHO）细胞。据估计，目前有900种生物药物正在进行临床试验，其中70%是在CHO细胞中制造的。该项目汇集了三个具有强大互补技能的不同团队，使该项目得以实现。首先，Alan Dickson教授（曼彻斯特大学）定义了CHO细胞可以改变的方面，以提高生物制药生产的效率和确定性。这些目标与缩短CHO细胞达到生产规模所需的时间和使细胞能够制造非天然产品（用于生产下一代生物制药）有关。Horizon Discovery已经建立了从细胞中添加和/或移除多个基因的技术，这项技术允许对CHO细胞进行基因工程改造，将CHO细胞重新设置为Dickson教授研究中定义的更理想的版本。Horizon方法将允许对CHO细胞进行多种组合改变，从而开发出一个包含细微不同细胞版本的工具箱，以应对许多处于研究阶段的新生物制药带来的挑战。最后，国家生物制品制造中心将对CHO细胞进行工程化改造，以提高其性能，并确定CHO细胞工具箱的潜力，以支持商业生产规模的现实生产潜力。一个强大的团队把假设变成现实去制造。

This project will enhance the manufacture of innovative medicines, allowing for more predictable routes to success and, with added certainty, enable the production of life-changing medicines more rapidly and cheaply with valuable consequences to patients and the economy. The focus is on improvement of the systems used to make medicines built from the knowledge of natural molecules, proteins, that are potent agents for the treatment of otherwise untreatable diseases. The molecules, often referred to as biopharmaceuticals (or biotherapeutics or biologics) are represented by insulin, a polymer of smaller components (amino acids) linked into a defined order by the genetic code in cells of the pancreas. The life-changing consequences of insulin in the treatment of diabetes is universally understood however it presents but one of many biopharmaceuticals that have been, are being/will be, made to treat diseases such as cancers (e.g Avastin), blood clotting disorders (e.g Factor VIII) or Rheumatoid arthritis (e.g Remicade). Each of these medicines is made by genetic engineering and they are synthesised by mammalian cells in fermenters. The research and safety validation of medicines of such wonderful potential is prolonged and costly but the rewards, for patients, society and economy are immense. Biopharmaceuticals dominate the pharmaceutical marketplace and in 2013, 7 of the top 10 selling drugs were biopharamcetuicals with combined sales of $58 billion. Potential rewards are immense but equally the investment is significant and consequently the cost to the patient and health agencies is high. There is a desire to make the route to market easier and less susceptible failure, to bring down the cost of manufacture and, hence, treatment. This situation is complicated by the development of new forms of biopharmaceuticals - molecules designed to be more specific, selective. potent and effective in treating diseases that until now have been untreatable. Many such biopharmaceuticals can be designed (for "theoretical" manufacture) but cannot be produced (or are produced poorly) by cells currently in industrial use. This presents the challenge to be addressed in the current project - making a new version of the cell used to manufacture the majority of the emerging biopharmaceuticals. The approach is novel, exciting and offers the potential to alter what is possible in the commercial production of biopharmaceuticals. The cell we will engineer into a new manufacturing platform is the Chinese Hamster Ovary (CHO) cell. Estimates suggest that 900 biopharmaceuticals are currently in clinical trials and 70% are being made in CHO cells, The project brings together three distinct groups with strong and complentary skills to make this project occur. Firstly, Professor Alan Dickson (University of Manchester) has defined aspects of the CHO cell that can be altered to increase the efficency and certainty of production of biopharmaceuticals. These targets are associated with shortening the time it takes for CHO cells to reach manufacturing scale and enabling cells to make non-natural products (for production of the next generation of biopharmaceuticals). Horizon Discovery has built the technologies to add and/or remove multiple genes from cells, a technology that permits CHO cells to be genetically engineered to re-set the CHO cell to the more desirable version defined by the studies of Professor Dickson. The Horizon approach will enable multiple changes to be made to CHO cells, in combinations, to develop a toolbox of subtly-different cell versions to address the challenges presented by the many new biopharmaceuticals at research stage. Finally, the National Biologics Manufacturing Centre will take CHO cells engineered for enhanced performance and define the potential of the toolbox of CHO cells to support real-life manufacturing potential at commercial maunfactruing scale. A strong team to take the hypothesis to reality to manufacture.