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

描述（由申请人提供）：只有13%的临床试验药物获得批准。75%的失败是由于在I期和II期临床试验中发现的意想不到的毒性或缺乏疗效。药物在后期开发的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一个症状。基于体外人体器官系统的技术有可能克服这些限制，使人体相关生理学能够在药物发现过程的早期进行研究。换句话说，开发基于人类生物学而非动物生物学的与生理更相关的体外系统，可能会更快地将药物推向市场，同时减少失败。这项工作的目的是产生冷冻保存的成人小肠细胞，并将这些细胞纳入肠-肝细胞共培养系统，该系统将更好地在体外系统中概括人类药物和毒物代谢。本项目的目标有两个：1)测试从尸体或新鲜空肠组织中冷冻保存和再生人小肠上皮的新方法的可行性；2)测试包含肠和肝代谢的多组织器官系统的可行性，使使用完全源自人体的产品进行药物功效和安全性测试以及工业化学品安全性测试的综合台式体外代谢模型成为可能

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