RECOMBINANT LEPTIN THERAPY FOR TREATMENT OF NASH

描述（由申请人提供）： 肥胖和胰岛素抵抗困扰着数百万美国人。在肥胖和胰岛素抵抗的新兴共病中，有一种称为非酒精性脂肪肝（NAFLD）的疾病。NAFLD的一种更具侵袭性的形式称为非酒精性脂肪性肝炎（NASH），其特征在于存在脂肪变性，炎症和不同程度的瘢痕形成。NASH可发展成肝硬化和永久性肝衰竭。使用应用程序主体中提供的数据和估计，美国至少有500万人患有NASH。因此，发现治疗NASH的有效策略将对美国的医疗保健成本产生重大影响。脂肪细胞激素瘦素被认为在调节肝脏中的脂质沉积中起作用，这是脂肪肝疾病的第一步。用瘦素治疗啮齿动物瘦素缺乏症可改善肝脏脂肪沉积。对人类脂肪营养不良和瘦素缺乏的研究表明，纠正瘦素缺乏除了逆转脂肪变性外，还导致细胞损伤的改善。这些观察结果保证了瘦素在NASH中的作用的研究。我们之前已经测定了已知脂肪肝患者的血清瘦素水平，并观察到约20%的NASH患者和高达40%的NASH男性患者表现出相对瘦素缺乏，使他们成为重组瘦素恢复治疗的理想候选人。在本研究中，我们将筛选BMI<40 kg/m2的非糖尿病男性患者的血清瘦素水平，这些患者被鉴定为患有活检证实的NASH。其中，我们将招募10名瘦素相对缺乏的受试者（对于他们的BMI和性别，水平<NHANES III水平的第25百分位数）用于重组人瘦素（Amgen，Thousand Oaks，加州）的治疗试验，其将以0.1 mg/kg/天的剂量皮下施用1年。1年结束时的肝脏组织病理学将是研究的主要结局。还将监测身体组成和代谢状态的参数。我们还将研究参与瘦素作用的潜在机制。大约100万美国人可能从这项研究应用的影响中直接受益，因为我们的目标是大约20%的NASH患者。

DESCRIPTION (provided by applicant): Obesity and insulin resistance afflict millions of Americans. Among emerging co-morbidities of obesity and insulin resistance, is a condition called nonalcoholic fatty liver disease (NAFLD). A more aggressive form of NAFLD is called nonalcoholic steatohepatitis (NASH), characterized by the presence of steatosis, inflammation and varying degrees of scarring. NASH can progress into cirrhosis and permanent liver failure. Using data and estimations to be presented within the body of the application, there are at least 5 million people in the US with NASH. Thus, discovery of effective strategies to treat NASH will make a big impact on health-care costs in the US. The adipocyte-hormone leptin is thought to play a role in modulating lipid deposition in the liver, the first step of fatty liver disease. Treatment with leptin in rodent leptin deficiency ameliorates fatty deposition in the liver. Studies in human lipodystrophy and leptin deficiency indicate that correction of leptin deficiency results in amelioration of cellular injury in addition to reversing steatosis. These observations warrant the investigation of leptin's role in NASH. We have previously determined serum leptin levels of patients with known fatty liver disease and observed that approximately 20% of patients with NASH and up to 40% of male patients with NASH demonstrate relative leptin deficiency, making them ideal candidates for restorative therapy with recombinant leptin. For this study, we will screen serum leptin levels of non-diabetic male patients with BMI<40kg/m2 who are identified as having biopsy proven NASH. Among those, we will enroll 10 subjects who are relatively leptin deficient (levels<25th percentile of NHANES III levels for their BMI and gender) for a therapeutic trial with recombinant human leptin (Amgen, Thousand Oaks, California) which will be administered subcutaneously at a dose of 0.1 mg/kg/day for 1 year. Liver histopathology at the end of 1 year will be the primary outcome of the study. Parameters of body composition and metabolic state will also be monitored. We will also investigate the potential mechanisms involved in leptin's action. Approximately 1 million Americans may derive direct benefit from the implications of this research application, since we are targeting approximately 20% of patients with NASH.