Swanson Kenneth D, Theodorou Evangelos, Kokkotou Efi
Preclinical Drug Evaluation Unit, Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Curr Opin Gastroenterol. 2018 Nov;34(6):384-391. doi: 10.1097/MOG.0000000000000485.
The medical management of inflammatory bowel disease (IBD) remains problematic with a pressing need for innovation in drug development as well as delivery of personalized therapies. Both the disease's inherent pathophysiologic complexity and heterogeneity in its etiology conspire in making it difficult to accurately model for either the purposes of basic research or drug development. Multiple attempts at creating meaningful experimental models have fallen short of adequately recapitulating the disease and most do not capture any aspect of the cause or the effects of patient heterogeneity that underlays most of the difficulties faced by physicians and their patients. In vivo animal models, tissue culture systems, and more recent synthetic biology approaches are all too simplistically reductionist for the task. However, ex vivo culture platforms utilizing patient biopsies offer a system that more closely mimics end-stage disease processes that can be studied in detail and subjected to experimental manipulations.
Recent studies describe further optimization of mucosal explant cultures in order to increase tissue viability and maintain a polarized epithelial layer. Current applications of the platform include studies of the interplay between the epithelial, immune and stromal compartment of the intestinal tissue, investigation of host-microbial interactions, preclinical evaluation of candidate drugs and uncovering mechanisms of action of established or emerging treatments for IBD.
Patient explant-based assays offer an advanced biological system in IBD that recapitulates disease complexity and reflects the heterogeneity of the patient population. In its current stage of development, the system can be utilized for drug testing prior to the costlier and time-consuming evaluation by clinical trials. Further refinement of the technology and establishment of assay readouts that correlate with therapeutic outcomes will yield a powerful tool for personalized medicine approaches in which individual patient responses to available treatments are assessed a priori, thus reducing the need for trial and error within the clinical setting.
炎症性肠病（IBD）的药物治疗仍然存在问题，迫切需要在药物研发以及个性化治疗的提供方面进行创新。该疾病固有的病理生理复杂性及其病因的异质性共同导致难以准确地为基础研究或药物研发目的建立模型。多次尝试创建有意义的实验模型都未能充分重现该疾病，并且大多数模型都没有捕捉到患者异质性的任何方面，而患者异质性正是医生及其患者面临的大多数困难的根源。体内动物模型、组织培养系统以及最近的合成生物学方法对于这项任务来说都过于简单化且还原论色彩过重。然而，利用患者活检组织的体外培养平台提供了一个更紧密模拟终末期疾病过程的系统，该系统可以进行详细研究并接受实验操作。
最近的研究描述了黏膜外植体培养的进一步优化，以提高组织活力并维持极化的上皮层。该平台目前的应用包括研究肠道组织上皮、免疫和基质区室之间的相互作用，调查宿主 - 微生物相互作用，对候选药物进行临床前评估以及揭示IBD既定或新兴治疗方法的作用机制。
基于患者外植体的检测方法为IBD提供了一个先进的生物系统，该系统概括了疾病的复杂性并反映了患者群体的异质性。在其当前的发展阶段，该系统可用于在进行成本更高且耗时的临床试验评估之前进行药物测试。进一步完善该技术并建立与治疗结果相关的检测读数，将产生一种强大的个性化医疗工具，通过该工具可以预先评估个体患者对现有治疗的反应，从而减少临床环境中反复试验的需求。
