Novel Pharmacological Strategies for Liver Disease in Antitrypsin Deficiency

描述(由申请人提供)：A1-抗胰蛋白酶(AT)缺乏的经典形式是儿童肝病最常见的遗传原因，也容易使成年人肝脏受损。在这种缺陷中，点突变导致肝脏分泌蛋白容易错误折叠和聚集。突变蛋白A1-抗胰蛋白酶Z(ATZ)积聚在肝细胞的内质网(ER)中，通过毒性作用机制引起炎症和癌变。研究人员现在知道，当突变蛋白在内质网中积累时，内质网的质量控制机构通过两种一般机制降解它：蛋白酶体途径负责处置可溶性ATZ，自噬途径负责处置保留在内质网中的不溶性聚集ATZ。推测突变ATZ的积累及其对肝脏的毒性作用反映了蛋白酶体和自噬处置途径不能处理突变蛋白负荷。在这项应用中，研究人员将使用新开发的AT缺乏症伴严重肝脏损害的基因工程小鼠模型来检验这一假说，即药物增强一次性途径的功能可以预防和改善AT缺乏症的肝病。本研究提出了三种新策略的初步证据，并将通过一系列临床前研究在小鼠模型中进一步检验这些策略：通过TOR激酶不依赖机制刺激胰岛素信号通路，增强ATZ的自噬处置；通过FDA已批准用于人类的药物刺激ATZ自噬处置，并且似乎通过非胰岛素和TOR激酶依赖机制发挥作用；使用对ATZ具有特定解聚作用的多肽刺激ATZ的蛋白酶体降解。这项申请中提出的研究有可能迅速进入治疗目前仅适用于肝移植治疗的肝病的药理策略的临床试验。 简介：本申请提出了三种新的药理策略的临床前研究，用于预防或治疗与A1-抗胰蛋白酶缺乏症相关的慢性肝炎和肝细胞癌，A1-抗胰蛋白酶缺乏症是儿童最常见的遗传性肝病。

DESCRIPTION (provided by applicant): The classical form of a1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children and also predisposes adults to liver damage. In this deficiency a point mutation renders a hepatic secretory protein prone to misfolding and aggregation. The mutant protein, a1-antitrypsin Z (ATZ), accumulates in the endoplasmic reticulum (ER) of liver cells, causing inflammation and carcinogenesis by a gain-of-toxic function mechanism. The investigators now know that there are two general mechanisms by which the quality control apparatus of the ER degrades this mutant protein when it accumulates in that compartment: the proteasomal pathway is responsible for disposal of soluble ATZ and the autophagic pathway is responsible for disposal of insoluble aggregated ATZ that is retained in the ER. Presumably the accumulation of mutant ATZ and its hepatotoxic effects reflect an inability of proteasomal and autophagic disposal pathways to handle the mutant protein load. In this application the investigators will examine the hypothesis that pharmacological enhancement of the function of the disposable pathways prevents and ameliorates the liver disease of AT deficiency using a newly developed genetically engineered mouse model of AT deficiency with severe liver damage. Preliminary evidence for three novel strategies is presented and will be further examined using a series of preclinical studies in the mouse model: stimulation of the insulin signaling pathway that enhances autophagic disposal of ATZ through a TOR kinase-independent mechanism; stimulation of autophagic disposal of ATZ by drugs that are already approved for use in humans by the FDA and appear to work by insulin-independent and TOR kinase-independent mechanisms; stimulation of proteasomal degradation of ATZ using a peptide with a specific depolymerizing effect on ATZ. The studies proposed in this application have the potential to rapidly move into clinical trials of pharmacological strategies for a liver disease that is currently only amenable to liver transplantation therapy. NARRATIVE: This application proposes preclinical studies of three novel pharmacological strategies for preventing or treating chronic hepatitis and hepatocellular carcinoma associated with a1-antitrypsin deficiency, the most common genetic liver disease of children.