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Optimising Product Quality of In Vitro Transcribed mRNA Therapeutics

优化体外转录 mRNA 疗法的产品质量

基本信息

批准号：
2280234
负责人：
金额：
--
依托单位：
University of Sheffield
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2280234
关键词：
Optimising Product Quality Vitro Transcribed

项目摘要

Gene therapy offers therapeutic promise for treating many currently incurable conditions, including cancers, neurological disorders and cardiovascular diseases. However, these therapies lack the enabling technologies that support development of other biopharmaceuticals, resulting in slow speed-to-clinic and/or poor product performance. For example, the production of mRNA for mRNA-based gene therapies is currently hampered by low yields and poor product qualities. These mRNA molecules are produced by in vitro transcription (IVT) systems that comprise four biological input components: the DNA template, an RNA polymerase, ribonucleoside triphosphates and a cap analogue/capping enzyme. The functionality of, and interplay between, these biological parts determines the rate of formation of both the 'correct' mRNA product, and undesirable product-related impurities, such as uncapped mRNA, long/short dsRNA, and long/short ssRNA molecules. These impurities significantly impact product quality, both by hampering mRNA performance (e.g. protein produced in vivo per mRNA dose) and activating potent, undesired immune responses. The unpredictable and uncontrollable formation of these molecules is therefore a critical obstacle to successfully translating IVT mRNA therapeutics into the clinic.This project will create new biological parts for production of IVT mRNAs, that are specifically designed to eliminate formation of product-related impurities, while also maximizing both system yield and batch-to-batch reproducibility.

基因疗法为治疗许多目前无法治愈的疾病提供了治疗前景，包括癌症、神经系统疾病和心血管疾病。然而，这些疗法缺乏支持其他生物药物开发的技术，导致临床速度缓慢和/或产品性能差。例如，用于基于mRNA的基因疗法的mRNA的生产目前受到低产率和差的产品质量的阻碍。这些mRNA分子由体外转录（IVT）系统产生，所述体外转录（IVT）系统包括四种生物输入组分：DNA模板、RNA聚合酶、核糖核苷三磷酸和帽类似物/加帽酶。这些生物学部分的功能性和它们之间的相互作用决定了“正确的”mRNA产物和不期望的产物相关杂质（例如未加帽的mRNA、长/短dsRNA和长/短ssRNA分子）的形成速率。这些杂质通过阻碍mRNA性能（例如，每mRNA剂量在体内产生的蛋白质）和激活有效的、不期望的免疫应答来显著影响产品质量。因此，这些分子的不可预测和不可控制的形成是成功将IVT mRNA疗法转化为临床的关键障碍。该项目将为IVT mRNA的生产创造新的生物部件，专门设计用于消除产品相关杂质的形成，同时最大限度地提高系统产量和批次间重现性。