Carbamazepine for severe liver disease due to antitrypsin deficiency

描述（由申请人提供）：在经典形式的11-抗胰蛋白酶（AT）缺乏症中，点突变改变了丰富的肝源性分泌糖蛋白的折叠，并使其易于聚合和聚集。突变蛋白，11-抗胰蛋白酶Z（ATZ），积累在肝细胞的内质网（ER）。“慢性ER超负荷”状态通过毒性功能获得机制导致肝纤维化/肝硬化和肝细胞癌。事实上，这种缺陷是儿童肝病最常见的遗传原因，也是成人肝硬化/癌症的相对常见原因。我的实验室一直在研究肝细胞激活突变ATZ的细胞内处置途径的机制，假设这些途径的功能变化可能解释纯合子之间肝病发病率和严重程度的变化，并且进一步，这些途径可能是潜在的药理学策略的目标。我们已经发现蛋白酶体负责降解突变ATZ的可溶形式，自噬专门用于处理不溶性聚合物和聚集体。由于自噬在ER中ATZ积累的细胞反应中的重要性，我们研究了增强自噬的药物是否可以改善这种疾病的肝毒性。从最近已被证明可以增强具有多聚谷氨酰胺重复序列的易聚集蛋白的自噬降解的药物列表中，我们选择卡马西平（CBZ）对其对ATZ的影响进行详细研究，因为它在人类中具有最广泛的安全性。结果表明，CBZ显着增加AT缺陷的细胞系模型中的突变ATZ的降解。此外，当口服给予AT缺乏的PiZ小鼠模型2周时，CBZ降低了ATZ在体内的肝负荷，并显着降低了肝纤维化。该提案的总体目标是确定CBZ是否可以有效治疗人类AT缺乏引起的肝脏疾病。在一项随机、双盲、安慰剂对照试验中，纯合子AT缺乏导致代偿性肝硬化的患者将接受CBZ治疗12个月。总体假设是CBZ治疗将通过增强其细胞内降解来降低肝ATZ负荷，从而减少肝纤维化和门脉高压。该假设将通过以下具体目的进行检验：1）确定CBZ治疗是否降低患有严重肝病的AT缺陷个体中的肝ATZ负荷; 2）确定CBZ治疗是否降低患有严重肝病的AT缺陷个体中的肝纤维化; 3）确定CBZ治疗是否降低患有严重肝病的AT缺陷个体中的门静脉压力。该试验还将确定CBZ是否能被患有严重肝病的患者耐受而没有严重的不良反应。

DESCRIPTION (provided by applicant): In the classical form of 11-antitrypsin (AT) deficiency a point mutation alters the folding of an abundant liver-derived secretory glycoprotein and also renders it prone to polymerization and aggregation. The mutant protein, 11-antitrypsin Z (ATZ), accumulates in the endoplasmic reticulum (ER) of liver cells. The 'chronic ER overload' state leads to hepatic fibrosis/cirrhosis and hepatocellular carcinoma by gain- of-toxic function mechanisms. Indeed, this deficiency is the most common genetic cause of liver disease in children and a relatively frequent cause of cirrhosis/carcinoma in adults. My lab has been studying the mechanisms by which hepatocytes activate pathways for intracellular disposal of the mutant ATZ with the hypothesis that variation in the function of these pathways might explain variation in incidence and severity of liver disease among homozygotes and, further, that these pathways might be targeted by potential pharmacotherapeutic strategies. We have found that the proteasome is responsible for degrading soluble forms of mutant ATZ and autophagy is specialized for disposal of the insoluble polymers and aggregates. Because of the importance of autophagy in the cellular response to accumulation of ATZ in the ER, we examined whether a drug that enhances autophagy could ameliorate hepatotoxicity in this disorder. From a list of drugs that have been recently shown to enhance autophagic degradation of aggregation-prone proteins with polyglutamine repeats, we selected carbamazepine (CBZ) for detailed studies of its effect on ATZ because it has the most extensive safety profile in humans. The results showed that CBZ dramatically increases degradation of mutant ATZ in cell line models of AT deficiency. Furthermore, when administered orally for 2 weeks to the PiZ mouse model of AT deficiency, CBZ decreased the hepatic load of ATZ in vivo and significantly reduced hepatic fibrosis. The overall objective of this proposal is to determine whether CBZ could be an effective treatment for liver disease due to AT deficiency in humans. Patients with compensated cirrhosis due to homozygous AT deficiency will be treated with CBZ for 12 months in a randomized, double-blinded, placebo-controlled trial. The overall hypothesis is that CBZ therapy will reduce the hepatic ATZ load by enhancing its intracellular degradation and, as a consequence, reduce hepatic fibrosis and portal hypertension. This hypothesis will be tested through the following specific aims: 1) Determine whether CBZ treatment reduces hepatic ATZ load in AT-deficient individuals with severe liver disease; 2) Determine whether CBZ treatment reduces hepatic fibrosis in AT- deficient individuals with severe liver disease; 3) Determine whether CBZ treatment reduces portal pressure in AT-deficient individuals with severe liver disease. The trial will also determine whether CBZ is tolerated by patients with severe liver disease without serious adverse effects.