GlycoCell Engineering Biology Mission Hub: Transforming glycan biomanufacture for health

GlycoCell 工程生物学任务中心：转变聚糖生物制造以促进健康

• 批准号: BB/Y008472/1
• 负责人: John Heap
• 金额: $ 1367.4万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY008472%2F1
• 关键词: GlycoCell; Engineering; Biology; Mission; Hub

Glycans or sugars have a huge impact on biological processes in all domains of life. Most medically important drugs are glyco-modified and vaccines often target the sugars on the surface of disease-causing pathogens. Hence, glycans play a key role in both biology and biotechnology. Optimising the expression and addition of sugars to proteins through glycoengineering offers an important avenue to creating lower cost, more effective vaccines, developing better therapies and diagnostics, and generating tools to more efficiently study health and disease. Glycans are difficult to study and manufacture and are considered the 'dark matter of biology'. This requires a new approach, and the advancement of Engineering Biology through our GlycoCell consortium is both timely and appropriate.GlycoCell builds on our glycotechnology and Engineering Biology expertise and previous successes with a vision to scale and deploy a 'GlycoForge' facility as a UK national asset. The GlycoForge combines high-throughput automation, elegant experiment design, and advanced mathematical methods to rapidly engineer cells to make new glycans. GlycoCell will develop and integrate cutting-edge technologies, train the current and next generations of researchers, attract industry, and drive value-adding translation with the wider research community. GlycoCell's targets will include bacterial and viral vaccines, as well as therapeutic proteins for treatment of other diseases. Vaccines are the most effective way to prevent infections and proven to reduce antimicrobial usage. The most successful vaccines against bacteria are glycoconjugates (glycans linked to proteins), which provide robust, lasting immunity in all age groups. Current glycoconjugate vaccine manufacture is costly and precludes use in resource poor settings or in veterinary medicine. We will efficiently produce novel vaccines. We will target the human pathogen Group A streptococci and animal pathogen Streptococcus uberis. We will test the limits of the GlycoForges with the efficient expression of 100 glycan variants of Streptococcus pneumoniae and a novel Coxiella vaccine that has an as yet unresolved glycan structure. We will undertake a simulated pandemic 'pressure test' to deliver a 100-day rapid epidemic response that will be important for UK preparedness. These vaccines will be produced in parallel in bespoke E. coli and Bacillus cells which have multiple advantages for vaccine development and manufacture. For therapeutic proteins, the glycan structure can dictate pharmacokinetics, protein turnover, and function. Most therapeutic glycoproteins are manufactured in mammalian hosts to match human glycan structures. These are costly to culture, challenging healthcare budgets and limiting patient access to therapies. We will use the GlycoForge to further develop bacteria and yeast cells to produce human-relevant glycans as novel therapeutics. This will include engineering Saccharomyces yeast cells able to mimic the glycosylation patterns of fungal pathogens, producing novel anti-fungal drugs. Pichia yeast cells will be used to produce novel viral vaccines including HIV and papilloma virus. This work will be supported by a world-leading facilities for analysis of glycans. Training and development of the current and next generations of researchers across the UK and beyond will be central to GlycoCell and will be deeply integrated into all activities. A training program in engineering biology led by both academics and industrial partners will occur over 5 years.GlycoCell will be led by an experienced management team and will be steered by an International Advisory Group to secure our vision to produce novel glycan-based medicines and to guide succession planning.

聚糖或糖对生命各个领域的生物过程都有巨大影响。大多数医学上重要的药物都是糖修饰的，疫苗通常针对致病病原体表面的糖。因此，聚糖在生物学和生物技术中发挥着关键作用。通过糖工程优化糖的表达和向蛋白质中添加糖，为创造更低成本、更有效的疫苗、开发更好的疗法和诊断方法以及生成更有效地研究健康和疾病的工具提供了重要途径。聚糖很难研究和制造，被认为是“生物学的暗物质”。这需要一种新的方法，而通过我们的 GlycoCell 联盟推进工程生物学既及时又恰当。GlycoCell 建立在我们的糖技术和工程生物学专业知识以及之前的成功基础上，其愿景是作为英国国家规模和部署“GlycoForge”设施资产。 GlycoForge 结合了高通量自动化、优雅的实验设计和先进的数学方法，可快速改造细胞以制造新的聚糖。 GlycoCell 将开发和整合尖端技术，培训当前和下一代研究人员，吸引行业，并与更广泛的研究界一起推动增值转化。 GlycoCell 的目标将包括细菌和病毒疫苗，以及用于治疗其他疾病的治疗蛋白。疫苗是预防感染最有效的方法，并被证明可以减少抗菌药物的使用。最成功的细菌疫苗是糖复合物（与蛋白质连接的聚糖），它为所有年龄段的人提供强大、持久的免疫力。目前的复合糖疫苗生产成本高昂，并且无法在资源匮乏的环境或兽医学中使用。 我们将高效生产新型疫苗。我们将针对人类病原体 A 组链球菌和动物病原体乳房链球菌。我们将通过有效表达 100 种肺炎链球菌聚糖变体和一种尚未解析聚糖结构的新型柯克斯体疫苗来测试 GlycoForges 的极限。我们将进行模拟大流行“压力测试”，以提供 100 天的快速流行病应对措施，这对于英国的准备工作非常重要。这些疫苗将在定制的大肠杆菌和芽孢杆菌细胞中并行生产，这对于疫苗开发和制造具有多种优势。对于治疗性蛋白质，聚糖结构可以决定药代动力学、蛋白质周转和功能。大多数治疗性糖蛋白是在哺乳动物宿主中制造的，以匹配人类聚糖结构。这些对文化来说成本高昂，对医疗保健预算构成挑战，并限制患者获得治疗的机会。我们将使用 GlycoForge 进一步开发细菌和酵母细胞，以生产与人类相关的聚糖作为新型疗法。这将包括改造酵母细胞，使其能够模仿真菌病原体的糖基化模式，从而生产新型抗真菌药物。毕赤酵母细胞将用于生产新型病毒疫苗，包括艾滋病毒和乳头状瘤病毒。这项工作将得到世界领先的聚糖分析设施的支持。英国及其他地区当前和下一代研究人员的培训和发展将成为 GlycoCell 的核心，并将深入融入所有活动中。由学术界和工业合作伙伴领导的工程生物学培训计划将在 5 年内进行。GlycoCell 将由经验丰富的管理团队领导，并由国际咨询小组指导，以确保我们生产新型聚糖药物的愿景，并指导继任计划。