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.

有效基因疗法的主要障碍包括在血流中快速中和，肝脏中的高库普弗细胞捕获以及靶细胞感染的低效率。靶向遗传修饰可以产生慢病毒载体变体，这些变体可能有可能克服这些障碍。但是，如果没有有效的测试系统可以比较新变体，误导性数据可能会导致不合适的变体用于临床开发。实际上，当前的临床前模型无法充分概括人类患者的规模和生理学。啮齿动物通常被使用，但是一个特别差的模型，循环速率比人类快13倍，肝内皮内皮的芬斯特雷距离比人宽30-60nm [Wisse，2008，GT]，血液体积和总质量比人类低3000倍，并且比人类低3000倍，并且病毒前曝光和血液细胞互补的受体的病史非常不同。我们有独特的位置，能够提供一个系统，即一种常规的灌注装置（NTPD），该系统可以维持体外的人体器官并允许使用治疗剂给药。连续的灌注可以采集血液和胆汁样品，以便可以定义器官功能/毒性和病毒载体药代动力学，同时通过在常规连接处进行的打孔组织活检对病毒基因组和转基因产物进行采样，还可以跟踪进入和集成水平。我们建议，与Oxford BioMedica合作，我们将使用NTPD介绍牛津生物组织中开发的新型慢病毒载体变体的PK。