Development of Gap Junction Inhibition Therapy for Alcoholic Liver Disease

 描述(申请人提供)：酒精性肝病是一种高度流行和代价高昂的疾病，影响着全球数百万人。酒精导致高发病率和死亡率，占全球所有死亡人数的近4%。尽管酒精性肝病造成了巨大的社会和经济负担，但目前还没有得到批准的治疗方法。相反，护理的标准涉及非特定皮质类固醇、免疫抑制剂和抗氧化剂的非标签管理。目前迫切需要可用于治疗急性和慢性酒精性肝病的肝脏特异性疗法。HeProtech的成立是为了将基于抑制肝脏缝隙连接通讯的治疗药物商业化。我们已经证明，由连接蛋白32(Cx32)组成的肝脏特异性缝隙连接在急性和慢性肝损伤的发病机制中是必不可少的。我们首先展示了抑制因子 Cx32缝隙连接保护和拯救小鼠免受药物诱导的肝毒性。接下来，我们发现这些Cx32缝隙连接抑制剂在饮食诱导的非酒精性脂肪性肝炎中具有保护作用。最近，我们的初步结果表明，Cx32缝隙连接在酒精性肝损伤中也是必不可少的。这项第一阶段SBIR赠款的总体目标是明确适当的临床背景，以抑制Cx32缝隙连接以保护酒精性肝损伤。在目标1中，我们将比较野生型和连接蛋白32缺陷小鼠急性和慢性酒精诱导的肝损伤。这将勾勒出新的Cx32靶点在急性和/或慢性酒精性肝损伤中是否重要。在目标2中，我们将研究我们的先导Cx32小分子抑制剂在急性和慢性酒精性肝损伤中的作用。这一努力的预期结果是澄清Cx32在急性损伤、慢性损伤或两者兼而有之中是否重要。其次，拟议的工作将提供早期证据，表明小分子抑制Cx32缝隙连接是治疗酒精性肝病的可行治疗策略。这些结果将为在SBIR计划的第二阶段期间进行的重点临床前研究的设计提供参考。

 DESCRIPTION (provided by applicant): Alcoholic liver disease is a highly prevalent and costly condition affecting millions of people globally. Alcohol results in high morbidity and mortality an is responsible for nearly 4% of all deaths worldwide. Despite the tremendous societal and economic burden, there is no approved therapeutics for alcoholic liver disease. Instead, the standard of care involves off-label administration of nonspecific corticosteroids, immunosuppressants, and antioxidants. There is a desperate need for liver-specific therapeutics that can be used to treat acute and chronic alcoholic liver disease. Heprotech was founded to commercialize therapeutics based on inhibition of gap junction communication in the liver. We have demonstrated that liver-specific gap junctions composed of connexin 32 (Cx32) are essential to the pathogenesis of acute and chronic liver injury. We first showed that inhibitors of Cx32 gap junctions protect and rescue mice from drug-induced hepatotoxicity. Next we found that these Cx32 gap junction inhibitors were protective in diet-induced nonalcoholic steatohepatitis. Most recently, our preliminary results suggest Cx32 gap junctions are also essential for alcohol-induced liver injury. The overall goal of this Phase I SBIR grant is to defin the appropriate clinical context for inhibiting Cx32 gap junctions for protection against alcohol-induced liver injury. In aim 1, we will compare acute and chronic alcohol-induced liver injury in wild type and connexin 32 deficient mice. This will delineate whether the novel Cx32 target is important in acute and/or chronic alcohol-induced liver injury. In aim 2, we will investigate our lead Cx32 small molecule inhibitor in acute and chronic alcohol-induced liver injury. The anticipated outcome of this effort is clarification of whether Cx32 is important in acute injury, chronic injury, or both. Secondly, the proposed work will provide early evidence that small molecule inhibition of Cx32 gap junctions is a viable therapeutic strategy for treatment of alcoholic liver disease. These results will inform the design of focused preclinical studies that will be performed during Phase II of this SBIR program.