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Myofibroblast-to-hepatocyte conversion as a therapy for alcoholic liver disease

肌成纤维细胞向肝细胞的转化作为酒精性肝病的治疗方法

基本信息

批准号：
8490228
负责人：
Holger Willenbring
金额：
$ 22.59万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8490228
关键词：
Adenovirus Vector Adenoviruses Adult Alcohol abuse Alcoholic Liver Diseases Alcohols Area Capsid Cardiac Cardiac Myocytes Cell Count Cell Therapy Cell Transplants Cells Cicatrix Clinical Clinical Trials Collagen Deposition Disease Engraftment Fibroblasts Fibrosis Fumarylacetoacetase Future Gene Transfer Generations Genome Genomics Heart Hepatic Hepatocyte Human In Vitro Infarction Libraries Liver Liver Failure Liver Fibrosis Liver diseases Metabolic Modeling Modification Mus Myofibroblast Organ Donor Outcome Pancreas Patients Pluripotent Stem Cells Production Rattus Recombinants Research Research Personnel Rest Retroviral Vector Source Tissues Toxic effect Toxin Translations Transplantation Treatment Efficacy Viral Viral Vector Viral hepatitis Work cell type effective therapy gene therapy helper-dependent adenoviral vector immunogenic improved improved functioning in vivo liver function liver transplantation mouse model novel therapeutics prevent public health relevance research study success transcription factor

项目摘要

DESCRIPTION (provided by applicant): Alcoholic liver disease eventually causes liver failure. The only curative therapy for patients with liver failure due to alcoholic liver disease is liver transplantation. Liver cell therapy is not effective in these patients because alcoholic liver disease is invariably associated with liver fibrosis, which impairs the engraftment of transplanted cells. Because of the long-standing shortage of donor livers, many patients with alcoholic liver disease die while waiting for liver transplantation. To improve the outcomes of these patients, we propose to work around liver fibrosis as a barrier to liver cell therapy. We hypothesize that the function of fibrotic livers can be improved by in vivo conversion of the cells that make up the fibrotic tissue into cells with hepatocyte function. Our hypothesis rests on the recent identification of hepatic transcription factors that can convert fibroblasts into therapeutically effective hepatocyte-like cells (iHeps) and success with in vivo conversion of fibrotic heart tissu into functional parenchyma. To establish in vivo iHep generation as a therapy for liver fibrosis, we will pursue 2 aims: (1) To convert myofibroblasts into iHeps in vivo. We will deliver the hepatic transcription factors to myofibroblasts with adenoviral vectors, which have been shown to efficiently transduce myofibroblasts in rat and mouse models of liver fibrosis. Most myofibroblasts are quiescent in advanced liver fibrosis, which will prevent loss of nonintegrating adenoviral vectors before conversion of myofibroblasts into iHeps is completed. Because myofibroblasts are the main source of collagen in the liver, our strategy is expected to not only increase the number of cells with hepatocyte function, but also prevent further collagen deposition in the liver. (2) To establish the use of nonintegrating adenoassociated viral (AAV) vectors for conversion of myofibroblasts into iHeps in vivo. Conventional adenoviral vectors are highly immunogenic and therefore not safe for human application. Because AAV vectors can persist in host cells without toxicity and integration into the genome, they are increasingly used for human gene therapy. To establish targeting of AAV vectors to liver myofibroblasts, we will screen a library of shuffled AAV capsids. In support of the feasibility of this approach, capsids targeting specifically pancreatic ¿-cells have recently been identified in this library. By improvig function and reducing fibrosis of the liver with a viral vector deemed safe for human application, the proposed strategy has potential as an alternative to liver transplantation for therapy of liver failure due to alcoholic liver disease.

描述（由申请人提供）：酒精性肝病最终会导致肝功能衰竭。酒精性肝病导致肝衰竭患者的唯一治疗方法是肝移植。肝细胞疗法对这些患者无效，因为酒精性肝病总是与肝纤维化相关，肝纤维化会损害移植物的植入细胞。由于供肝长期短缺，许多酒精性肝病患者在等待肝移植过程中死亡。为了改善这些患者的治疗结果，我们建议解决肝纤维化作为肝细胞治疗的障碍。我们假设纤维化肝脏的功能可以通过构成肝脏的细胞的体内转化来改善。纤维化组织转变为具有肝细胞功能的细胞。我们的假设基于最近鉴定的肝转录因子，这些转录因子可以将成纤维细胞转化为治疗有效的肝细胞样细胞（iHeps），并成功地将纤维化心脏组织体内转化为功能性实质细胞。为了建立体内 iHep 生成作为肝纤维化的治疗方法，我们将追求两个目标：（1）在体内将肌成纤维细胞转化为 iHeps。我们将用腺病毒载体将肝转录因子递送至肌成纤维细胞，该载体已被证明可以在大鼠和小鼠肝纤维化模型中有效转导肌成纤维细胞。大多数肌成纤维细胞在晚期肝纤维化中处于静止状态，这将在肌成纤维细胞转化为 iHeps 完成之前防止非整合腺病毒载体的丢失。由于肌成纤维细胞是肝脏中胶原蛋白的主要来源，因此我们的策略预计不仅可以增加具有肝细胞功能的细胞数量，而且可以防止肝脏中胶原蛋白的进一步沉积。 (2) 建立非整合腺相关病毒 (AAV) 载体在体内将肌成纤维细胞转化为 iHeps 的用途。传统的腺病毒载体具有高度免疫原性，因此对人类应用不安全。由于 AAV 载体可以在宿主细胞中持续存在而无毒性并整合到基因组中，因此它们越来越多地用于人类基因治疗。为了建立 AAV 载体对肝肌成纤维细胞的靶向，我们将筛选改组的 AAV 衣壳文库。为了支持这种方法的可行性，最近在该文库中鉴定出了专门针对胰腺 ¿ 细胞的衣壳。通过使用被认为对人类应用安全的病毒载体改善肝脏功能并减少肝脏纤维化，所提出的策略有可能作为肝脏移植治疗肝脏的替代方案因酒精性肝病而失败。