Cellular Composite Device for Combination Therapy of Acute Liver Failure

用于急性肝衰竭联合治疗的细胞复合装置

基本信息

批准号：
8063890
负责人：
Martin L Yarmush
金额：
$ 26.25万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-20 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8063890
关键词：
Acute Liver Failure Affect American Amino Acids Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Artificial Liver Bioreactors Blood Circulation Cause of Death Cell physiology Cell secretion Cells Cessation of life Chemicals Chronic Cirrhosis Coculture Techniques Combined Modality Therapy Cytoprotection Devices Dialysis procedure Effectiveness Engineering Equipment Malfunction Etiology Family suidae Foundations Functional disorder Galactosamine Glucagon Goals Gold Growth Hepatic Hepatocyte Hospitals Hour Human Immune system Immunosuppression In Vitro Inflammation Inflammatory Response Insulin Life Liver Liver Failure Liver diseases Malignant neoplasm of liver Measures Mesenchymal Stem Cells Metabolic Metabolism Modeling Onset of illness Organ Organ Donor Organ failure Pathologic Processes Patients Pattern Phase Plasma Population Growth Property Protocols documentation Rattus Regulation Research Design Rodent Rodent Model Scheme Seeds Sepsis Serological Serum Simulate Staging Supplementation Technology Testing Therapeutic Therapy Clinical Trials Time Transplantation United Network for Organ Sharing United States Validation Waiting Lists base cell type cohort cost design effective therapy hepatotoxin in vivo liver transplantation mathematical model operation prevent prototype public health relevance scale up

项目摘要

DESCRIPTION (provided by applicant): Liver failure is the 7th leading cause of death and is responsible for 50,000 deaths per year in the United States. Orthotopic liver transplantation is the only proven effective treatment of acute liver failure (ALF), but its use is limited due to organ donor shortage, associated high costs, and the requirement of lifelong immunosuppression. The present and expected growth of the population that is affected by liver failure is ever rising and a life-saving alternative to transplantation is needed to support patients. Bioartificial liver devices are a rational approach to support ALF patients as a bridge to transplantation. Five cell- based devices have been tested in humans and pigs and appear safe, but none have shown a survival benefit. The failure of devices to-date suggests an ineffective mechanism of action. End-stage liver failure leads to systemic dysfunction that is occurring simultaneously with an inflammatory response. We hypothesize that a combination approach to therapy that provides hepatocellular support along with cytoprotection, anti-inflammatory, and trophic support will cover the broad spectrum of pathological processes that can stabilize a patient. In proof-of-principle therapeutic trials, we have demonstrated that human mesenchymal stem cell (MSCs) naturally secrete bioactive molecules that have immunomodulatory properties. We have developed MSC-based devices that are operated outside the body and connect to a subject's circulation to provide long-term support, and have shown that when connected to one of these devices for 10 hours, rats undergoing ALF have a 5-fold increase in survival from less than 15% to over 70%. The overall goal of this Phase I project is to develop a composite cellular bioreactor for the treatment of ALF that integrates both hepatocyte and MSC metabolism and secretion in a single unit, and evaluate the added benefit of this two-cell device over and above the effectiveness of the MSC devices. The project specific aims are: (1) To optimize the in vitro coculture of MSCs and hepatocytes and simulate the effect of liver failure serum on the function of the coculture; and (2) To incorporate MSCs and hepatocytes into flat-plate devices and initiate therapeutic testing of bioreactor treatments in rodent models. Upon successful completion of this project, the deliverable will be a prototype cell-laden dialysis cartridge that can be readily scaled up and tested in large animals. PUBLIC HEALTH RELEVANCE: We propose to develop an extracorporeal bioartificial liver device that offers unparalleled support to patients undergoing liver failure. The device will contain hepatocytes and mesenchymal stem cells (MSCs). The addition of MSCs is unique to our technology and is designed to enhance the metabolic functions of hepatocytes exposed to plasma and restore the regulation of the dysfunctional immune system in patients undergoing liver failure by active MSC secretion anti-inflammatory and trophic molecules. This two-pronged approach distinguishes this device from current prototypes. Our objectives are to perform in vitro optimization of the coculture using metabolic engineering of the coculture and in vivo testing of a microfabricated coculture device in two rat models of liver failure. These studies will determine if the combination therapeutic approach can be indicated for a broad range of liver disease etiologies and will motivate testing in large animal models of liver failure, and ultimately in human patients.

描述（由申请人提供）：肝衰竭是第七大死亡原因，在美国造成每年50,000人死亡。原位肝移植是急诊急性肝衰竭（ALF）的唯一有效治疗方法，但由于器官捐献者短缺，相关的高成本以及对终身免疫抑制的需求，其使用受到限制。受肝衰竭影响的人口的目前和预期的增长始终在上升，需要挽救生命的移植替代品来支持患者。生物人工肝脏装置是支持ALF患者作为移植的桥梁的合理方法。已经在人类和猪中测试了五个基于细胞的设备，并且看起来很安全，但是没有一个显示生存益处。迄今为止，设备的失败表明了一种无效的作用机理。末期肝衰竭会导致全身功能障碍，并同时发生炎症反应。我们假设一种提供肝细胞支持以及细胞保护，抗炎和营养支持的治疗方法将涵盖可稳定患者的广泛病理过程。在原则治疗试验中，我们已经证明了人间充质干细胞（MSC）自然地分泌具有免疫调节特性的生物活性分子。我们已经开发了基于MSC的设备，这些设备在体外运行并连接到受试者的循环以提供长期支持，并表明，当与这些设备之一连接10个小时时，接受ALF的大鼠的生存率从不到15％到70％以上。该阶段I项目的总体目标是开发一个复合细胞生物反应器，用于治疗ALF，该ALF将肝细胞和MSC代谢和分泌在单个单元中整合，并评估该两组设备的额外好处，而不是MSC设备的效率。该项目的特定目的是：（1）优化MSC和肝细胞的体外共培养物，并模拟肝衰竭血清对共培养功能的影响；（2）将MSC和肝细胞纳入平板设备中，并在啮齿动物模型中启动生物反应器处理的治疗测试。成功完成该项目后，可交付的将是一个原型型细胞透析弹药筒，可以在大型动物中很容易缩放和测试。公共卫生相关性：我们建议开发一种体外生物人工肝脏装置，为患有肝衰竭的患者提供无与伦比的支持。该设备将包含肝细胞和间充质干细胞（MSC）。 MSC的添加是我们技术独有的，旨在增强暴露于等离子体的肝细胞的代谢功能，并恢复活跃的MSC分泌抗炎和营养分子的肝衰竭患者中功能障碍免疫系统的调节。这种两管齐的方法将该设备与当前原型区分开。我们的目标是使用共培养的代谢工程和在两种大鼠肝脏衰竭模型中对合作培养的代谢工程进行体外优化共培养。这些研究将确定是否可以针对广泛的肝病病因来指示组合治疗方法，并激励大型肝衰竭模型以及最终在人类患者中进行测试。