Treatment for alcoholic liver disease

酒精性肝病的治疗

基本信息

批准号：
8200028
负责人：
Bert J. W. M. Oehlen
金额：
$ 82.91万
依托单位：
ANGION BIOMEDICA CORPORATION
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：
2010-09-15 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8200028
关键词：
Adverse event Alcohol consumption Alcoholic Hepatitis Alcoholic Liver Diseases Alcoholic liver damage Apoptosis CCL4 gene Canis familiaris Cardiovascular system Cause of Death Cell Proliferation Chromosome abnormality Chronic Cicatrix Cirrhosis Clinical Country Cytochrome P450 Data Development Disease Dose Drug Exposure Drug Interactions Enzymes Excretory function Female Grant Hepatocyte In Vitro Injury to Liver Ion Channel Kilogram Lead Liver Liver Cirrhosis Liver Fibrosis Lymphoma Medical Messenger RNA Metabolism Microsomes Modeling Molecular Mus Neurologic Oral P-Glycoprotein Patients Pharmaceutical Preparations Property Rattus Recombinants Research Rodent Safety Sampling Series Serum Signal Transduction Staging Techniques Testing Therapeutic Therapeutic Index Time Tissue Sample Toxicology Transcript Tretinoin United States Western Blotting Work absorption analytical method drug candidate effective therapy in vivo in vivo Model inhibitor/antagonist male method development micronucleus novel pre-clinical preclinical efficacy problem drinker receptor respiratory

项目摘要

DESCRIPTION (provided by applicant): Liver fibrosis is a form of scar formation that is found in almost all patients with chronic injury to the liver. Over time it frequently progresses to cirrhosis, an end-stage lethal disease which is the seventh leading cause of death in the United States and afflicts hundreds of millions of people worldwide. Alcohol intake remains the most important cause of liver cirrhosis in Western countries. Alcoholic liver disease can be divided in various stages of development: (1) mild alcoholic liver injury, (2) steatosis, (3) alcoholic hepatitis, (4) alcoholic liver fibrosis and (5) cirrhosis. Although several pharmacological therapies have been tried in patients with alcoholic liver disease, none of the therapeutics so far has shown consistent improvement in the course of alcoholic liver damage and there remains a major unmet medical need for effective therapies. In our preliminary data, we show that modulators of endogenous ATRA levels have anti-fibrotic activity in mice. We have identified a novel series of ATRA modulators with excellent in vitro and in vivo pharmacological properties and demonstrate its anti-fibrotic activity in vivo. We propose to pursue the lead compound from this series towards an IND nomination as a potential therapeutic for alcoholic liver disease. PUBLIC HEALTH RELEVANCE: Liver fibrosis is a form of scar formation that is found in almost all patients with chronic injury to the liver caused by sustained immoderate alcohol consumption. Over time it frequently progresses to cirrhosis, an end- stage lethal disease which is the seventh leading cause of death in the United States and afflicts hundreds of millions of people worldwide. There is no therapeutic that shows consistent improvement in the course of alcoholic liver damage and there remains a major unmet medical need for effective therapies. In our preliminary data, we show that modulators of endogenous ATRA levels have anti-fibrotic activity in mice and that we have identified a novel, in vivo efficacious, series of ATRA modulators. We propose to pursue the lead compound from this series towards an IND nomination as a potential therapeutic for alcoholic liver disease.

描述（由申请人提供）：肝纤维化是一种疤痕形成形式，几乎所有患有慢性肝脏损伤的患者都会发现这种情况。随着时间的推移，它经常发展为肝硬化，这是一种终末期致命疾病，是美国第七大死因，困扰着全世界数亿人。在西方国家，酒精摄入仍然是导致肝硬化的最重要原因。酒精性肝病可分为不同的发展阶段：（1）轻度酒精性肝损伤，（2）脂肪变性，（3）酒精性肝炎，（4）酒精性肝纤维化和（5）肝硬化。尽管已经在酒精性肝病患者中尝试了几种药物疗法，但迄今为止没有一种疗法能够在酒精性肝损伤过程中显示出持续的改善，并且对有效疗法的医疗需求仍然未得到满足。在我们的初步数据中，我们表明内源性 ATRA 水平调节剂在小鼠中具有抗纤维化活性。我们已经鉴定出一系列新型 ATRA 调节剂，具有优异的体外和体内药理学特性，并证明了其体内抗纤维化活性。我们建议将该系列的先导化合物作为酒精性肝病的潜在治疗药物进行 IND 提名。公共健康相关性：肝纤维化是一种疤痕形成形式，几乎所有因持续过量饮酒而导致肝脏慢性损伤的患者都会出现这种情况。随着时间的推移，它经常发展为肝硬化，这是一种终末期致命疾病，是美国第七大死因，困扰着全世界数亿人。目前还没有一种治疗方法能够持续改善酒精性肝损伤的过程，并且对于有效治疗的医疗需求仍然存在未得到满足的重大问题。在我们的初步数据中，我们表明内源性 ATRA 水平的调节剂在小鼠中具有抗纤维化活性，并且我们已经鉴定出一系列新型的、体内有效的 ATRA 调节剂。我们建议将该系列的先导化合物作为酒精性肝病的潜在治疗药物进行 IND 提名。