Use of normo-thermic perfused organs to profile PK and infection efficiency of novel viral gene therapy vectors.

使用常温灌注器官来分析新型病毒基因治疗载体的 PK 和感染效率。

• 批准号: 2891748
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2891748
• 关键词: Use; normo; thermic; perfused; organs

Major barriers to effective gene therapy include rapid neutralisation in the blood stream, high Kupffer cell capture in the liver and low efficiency of target cell infection. Targeted genetic modification can generate lentiviral vector variants which may have the potential to overcome these barriers. However, without valid test systems with which to compare new variants, misleading data may result in unsuitable variants being prioritised for clinical development. Indeed, current pre-clinical models fail to adequately recapitulate the scale and physiology of human patients. Rodents are commonly used but are a particularly poor model, with a circulation rate 13x faster than humans, liver endothelial fenestrae gaps 30-60nm wider than in humans [Wisse,2008,GT], a blood volume and total mass 3000x lower than humans, and a very different history of virus pre-exposure and blood cell complement receptor profile [Carlisle,2009,Blood]. We are uniquely positioned to be able to provide a system, a normothermic perfusion device (NTPD), which can maintain human organs outside the body and permit their dosing with therapeutic agents. Continuous perfusion allows for blood and bile samples to be taken so that organ function/toxicity and viral vector pharmacokinetics can be defined, whilst sampling for virus genomes and transgene products by punch tissue biopsies taken at regular junctures can also track rates and levels of entry and integration. We propose that, in collaboration with Oxford Biomedica, we will use the NTPD to profile the PK of novel Lentiviral vector variants developed in Oxford Biomedica.

有效基因治疗的主要障碍包括血流中的快速中和、肝脏中库普弗细胞的高捕获以及靶细胞感染的低效率。有针对性的基因改造可以产生慢病毒载体变体，这可能有克服这些障碍的潜力。然而，如果没有有效的测试系统来比较新变异，误导性数据可能会导致不合适的变异被优先用于临床开发。事实上，当前的临床前模型无法充分概括人类患者的规模和生理机能。啮齿类动物很常用，但模型特别差，其循环速度比人类快 13 倍，肝内皮窗孔间隙比人类宽 30-60 nm [Wisse,2008,GT]，血容量和总质量比人类低 3000 倍，以及病毒预暴露史和血细胞补体受体特征的非常不同的历史[Carlisle，2009，Blood]。我们拥有独特的优势，能够提供常温灌注装置 (NTPD) 系统，该系统可以将人体器官维持在体外，并允许对其进行治疗药物的给药。连续灌注允许采集血液和胆汁样本，以便可以定义器官功能/毒性和病毒载体药代动力学，同时通过定期进行穿刺组织活检来采样病毒基因组和转基因产物，还可以跟踪进入和传播的速率和水平。一体化。我们建议与 Oxford Biomedica 合作，利用 NTPD 来分析 Oxford Biomedica 开发的新型慢病毒载体变体的 PK。