Treatment for alcoholic liver disease

描述（由申请人提供）：肝纤维化是一种瘢痕形成形式，几乎在所有肝脏慢性损伤患者中都有发现。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，是美国第七大死亡原因，折磨着全世界数亿人。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治疗方法，但迄今为止，没有一种治疗方法在酒精性肝损伤的过程中显示出持续的改善，对有效治疗的医学需求仍未得到满足。有大量证据表明，正常肝功能和肝脏再生需要全反式维甲酸（ATRA）。ATRA可预防和逆转动物肝纤维化的进程。一些研究表明，体内抑制某些细胞色素P450酶可以提高内源性ATRA水平，并在皮肤和肿瘤动物模型中导致类维甲酸活性。细胞色素P450酶视黄酸4-羟化酶被认为是参与ATRA分解代谢的关键酶。在我们的初步数据中，我们发现维甲酸4-羟化酶抑制剂在taa诱导的小鼠肝纤维化模型中显示出活性，从而为其作为肝纤维化治疗药物的潜在用途建立了新的概念证明。我们的长期目标是开发维甲酸4-羟化酶的小分子抑制剂，作为酒精性肝病的潜在治疗药物。本申请的目的是鉴定这些抑制剂，并在两种临床相关的肝纤维化动物模型中评估它们。

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. There is a significant body of evidence implicating a requirement for All Trans Retinoic Acid (ATRA) for normal liver function and in liver regeneration. ATRA administration can prevent and reverse the course of liver fibrosis in animal models. Several studies have shown that inhibition of certain cytochrome P450 enzymes in vivo can boost endogenous ATRA levels and result in retinoid-like activity in dermatological and oncological animal models. The cytochrome P450 enzyme retinoic acid 4-hydroxylase is thought to be the key enzyme involved ATRA catabolism. In our preliminary data, we show that an inhibitor of retinoic acid 4-hydroxylase shows activity in a mouse model of TAA-induced liver fibrosis in mice, thus establishing a novel proof of concept for their potential use as therapeutics for liver fibrosis. Our long-term goal is the development of small molecule inhibitors of retinoic acid 4-hydroxylase as potential therapeutics for alcoholic liver disease. The objective of this application is to identify such inhibitors and evaluate them in two clinically relevant animal models of liver fibrosis. 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. There is a significant body of evidence implicating a requirement for All Trans Retinoic Acid (ATRA) for normal liver function and in liver regeneration. We intend to develop of small molecule inhibitors of retinoic acid 4- hydroxylase that can elevate the body's ATRA levels as a potential therapeutic for alcoholic liver disease.