Carbamazepine for severe liver disease due to antitrypsin deficiency

描述(申请人提供)：在11-抗胰蛋白酶(AT)缺乏症的经典形式中，点突变改变了丰富的肝脏来源的分泌型糖蛋白的折叠，也使其易于聚合和聚集。突变蛋白11-抗胰蛋白酶Z(ATZ)积聚在肝细胞的内质网(ER)中。“慢性内质网超负荷”状态通过毒性作用机制导致肝纤维化/肝硬变和肝细胞癌。事实上，这种缺陷是儿童肝病最常见的遗传原因，也是成人肝硬变/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以解释纯合子肝病的发病率和严重程度的差异，进一步说，这些途径可能是潜在的药物治疗策略的靶点。我们发现，蛋白酶体负责降解突变的ATZ的可溶性形式，而自噬专门用于处理不溶的聚合物和聚集体。由于自噬在细胞对内质网中ATZ积聚的反应中的重要性，我们检查了增强自噬的药物是否可以减轻这种疾病的肝毒性。从最近被证明可以增强具有多个谷氨酰胺重复序列的聚集倾向蛋白的自噬降解的药物清单中，我们选择了卡马西平(CBZ)来详细研究其对ATZ的影响，因为它在人类中具有最广泛的安全性。结果表明，在AT缺乏的细胞系模型中，CBZ显著增加突变ATZ的降解。此外，对于AT缺乏的PIZ小鼠模型，口服CBZ 2周后，CBZ可降低体内ATZ的肝负荷，并显著减轻肝纤维化。这项建议的总体目标是确定卡马西平是否可以有效治疗人类AT缺乏症引起的肝病。在一项随机、双盲、安慰剂对照试验中，因AT缺乏而导致代偿性肝硬变的患者将接受CBZ为期12个月的治疗。总体假设是，CBZ治疗将通过促进其细胞内降解来降低肝脏ATZ的负荷，从而减少肝纤维化和门脉高压。这一假设将通过以下具体目标得到验证：1)确定卡巴唑治疗是否降低了患有严重肝病的AT缺乏患者的肝脏ATZ负荷；2)确定卡巴唑治疗是否减少了患有严重肝病的AT缺乏患者的肝纤维化；3)确定CBZ治疗是否降低了患有严重肝病的AT缺乏患者的门静脉压力。这项试验还将确定严重肝病患者是否可以耐受CBZ，而不会产生严重的不良反应。 公共卫生相关性：该申请提出了一项临床试验，以确定卡马西平是否可以用于治疗由于11-抗胰蛋白酶缺乏症引起的严重肝病，这是目前儿童接受肝移植最常见的遗传性疾病。

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. PUBLIC HEALTH RELEVANCE: This application proposes a clinical trial to determine whether carbamazepine can be used to treat severe liver disease due to 11-antitrypsin deficiency, the most common genetic disease for which children currently undergo liver transplantation.