Optimising Product Quality of In Vitro Transcribed mRNA Therapeutics

点击翻译按钮获取中文摘要

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.