Bench-top human metabolism system for improved IVIVE in drug development

描述（由申请人提供）：只有13%的进入临床试验的研究药物获得批准。这些失败中有75%是由于I期和II期临床试验中发现的意外毒性或缺乏疗效。药物在后期开发阶段的这种高失败率是临床前动物模型不足以准确预测人类生物学的症状。基于体外人体器官系统的技术有可能通过在药物发现过程中更早地研究人类相关生理学来克服这些限制。换句话说，基于人类生物学而不是动物生物学的更具生理相关性的体外系统的开发可能会更快地将药物推向市场，减少失败。这项工作的目的是生产冷冻保存的成年人小肠细胞，并将这些细胞纳入到一个牛磺酸-肝细胞共培养系统，这将更好地重演人类药物和毒物的代谢在体外系统。本课题的目的有两个：1）研究一种新的人小肠上皮细胞冻存和复苏方法的可行性，该方法可以从尸体来源或新鲜来源的空肠组织中获得; 2）测试结合肠和肝代谢的多组织器官系统的可行性，以实现使用完全人的综合台式体外代谢模型。用于药物功效和安全性测试以及工业化学品安全性测试的衍生产品

DESCRIPTION (provided by applicant): Only 13% of investigational drugs that enter clinical trials make it to approval. Seventy-five percent of these failures are due to either unexpected toxicity or lack of efficacy discovered in phase I and II clinical trials. This high failure rate o drugs in late stage development is a symptom of the inadequacy of pre- clinical animal models to accurately predict human biology. Technologies based on human organ systems in vitro has the potential to overcome these limitations by enabling human relevant physiology to be studied earlier in the drug discovery process. In other words, development of more physiologically relevant in vitro systems grounded in human biology rather than animal biology could potentially bring drugs to market faster with fewer failures. The purpose of this work is to produce cryopreserved adult human small intestinal cells and incorporate those cells into an intestine-hepatocyte co-culture system that will better recapitulate human drug and toxicant metabolism in an in-vitro system. The goals of this proposed project are twofold: 1) Test feasibility of a novl approach for cryopreservation and reanimation of human small intestinal epithelium from either cadaver derived or fresh derived jejunum tissue; 2) Test feasibility of a multi-tissue organ systems incorporating both intestine and liver metabolism to enable a comprehensive benchtop in vitro metabolism model using entirely human- derived products for pharmaceutical efficacy and safety testing as well as industrial chemical safety testing