Engineering Viral Vector Biomanufacturing for Gene Therapy

基因疗法利用工程的非致病病毒(如腺相关病毒，AAV)作为载体，将治疗性基因输送到人体，可以纠正支撑疾病的基因变化。这种方法可能适用于人体的多个器官，先进的治疗方法已经在临床试验中成功地进行了研究，例如，治疗各种遗传疾病和癌症。新的基因疗法开始被批准用于临床。2019年，所有病毒载体临床试验中有73%是在英国进行的，其中89%使用了AAV。据估计，到2027年，基因治疗的市场将达到3600亿美元，复合年增长率为36%。然而，AAVs等病毒是由许多成分组成的复杂分子组件，难以制造，依赖于在受控培养过程中将合成的基因成分引入哺乳动物细胞以制造病毒，然后进行纯化和产品质量分析。低产量和缺乏治疗基因有效载荷的病毒生产是制造工艺开发的地方性问题；目前英国制造适合人类治疗的病毒载体的设施不能满足需求，因此严重阻碍了令人兴奋的基因疗法转化为临床试验。迫切需要新的技术来强化生产高质量的病毒基因疗法。该项目属于EPSRC主题制造未来和医疗技术的范围。关于后者，开发未来疗法是一个确定的问题。这是个伟大的挑战。

Gene therapies utilise engineered, non-pathogenic viruses (such as adeno-associated virus, AAV) as vehicles to deliver therapeutic genes to the human body that can correct genetic changes underpinning disease. This approach is potentially applicable to multiple organs of the human body, and the advanced therapies have been successfully studied in clinical trials for the treatment of, for example, a wide variety of genetic disorders and cancers. New gene therapies are beginning to be approved for use in the clinic. In 2019 73% of all viral vector clinical trials were based in the UK, 89% of which utilised AAV. It is estimated that the market for gene therapies will reach 36B USD by 2027 with a compound annual growth rate of 36%.However, viruses such as AAVs are complex molecular assemblies of numerous components which are difficult to manufacture, relying on introduction of synthetic genetic components into mammalian cells in controlled culture processes for virus manufacture, followed by purification and analysis of product quality. Low product yields and production of viruses lacking the therapeutic gene payload are endemic problems for manufacturing process development; current UK facilities for manufacturing viral vectors suitable for human treatment cannot meet demand, thus seriously hindering the translation of exciting gene therapies into clinical trials. New technology for intensified production of high quality viral gene therapies is urgently required.This project is within the scope of the EPSRC themes Manufacturing the Future and Healthcare Technologies. With respect to the latter, Developing Future Therapies is an identified. grand challenge.