A novel approach to treat non-alcoholic steatohepatitis (NASH)

摘要 此SBIR快速通道应用程序的目标是对我们的siRNA药物进行多项IND支持研究 候选药物，用于治疗非酒精性脂肪性肝炎(NASH)。NASH是一种非酒精脂肪 肝脏疾病(NAFLD)是肝脏脂肪病理性堆积的结果。大约500万 仅在美国就有人被诊断出患有NASH。NASH可导致肝硬变，随后是肝功能衰竭或 肝细胞癌。预计全球确诊的NASH患者数量约为1600万。这个 目前NASH的主要治疗方法是改变生活方式。然而，很少有患者长期依从性。 一段时间。美国或其他国家尚未批准用于治疗NASH的药物。 为了解决这一未得到满足的医疗需求，我们正在采取创新的方法治疗NASH，通过增加 肝脏中的线粒体代谢。脂肪酸被运输到肝脏，在那里它们被代谢 线粒体通过氧化，它与电子传递链(ETC)和线粒体相连 呼吸。因此，增加肝脏中ETC的活性可以加速脂肪酸的降解 并防止它们在肝脏中积聚。ETC的一个关键的内源性负性调节因子是MCJ蛋白 (MCJ/Dna JC15或甲基化控制的J蛋白)。MCJ是一种线粒体蛋白，它起到刹车的作用 ETC(“线粒体内制动”)。我们已经证明，去除MCJ是安全的，结果是增加了 线粒体呼吸作用不增加活性氧物种的产生。这是因为移除 MCJ通过促进呼吸超复合体的形成，最大限度地减少电子泄漏。 在初步研究中，我们使用小鼠特异性siRNA来显示我们方法的安全性和逆转的有效性。 以及使用NASH的多个小鼠模型预防与NASH相关的病理。小干扰RNA 已经被验证为治疗多种疾病的药物，最近FDA批准了两种siRNA药物用于 肝病的治疗(帕西兰和吉沃西兰)。此外，GalNAc(N-乙酰半乳糖胺)已被 临床上用于将siRNA定向到肝细胞。我们已经确定了一种能够交叉反应的前导siRNA 人、NHP和小鼠MCJ。我们还开发了专有的GalNAc载体和领先的siRNA-GalNAc 配方(Mito-1041)，但该配方尚未在NASH模型中进行测试或罕见出现 多核苷酸对肝脏的毒性。在第一阶段，我们将测试毒性和疗效。后备化合物也 已被确定为降低该计划的风险。在第一阶段成功后，我们将向美国国立卫生研究院申请第二阶段资金。在……里面 在第二阶段，我们将按照NIDDK的建议，开展一些支持IND的研究。继成功的 在这些研究中，我们将提交SBIR IIb阶段的建议，以制造GMP材料，进行最终的GLP 在大鼠和NHP上进行毒素研究，提交IND，并进行人类第一阶段临床研究。

Abstract The goal of this SBIR fast-track application is to carry out a number of IND enabling studies on our siRNA drug candidate, which is designed to treat non-alcohol steatohepatitis (NASH). NASH is a form of non-alcohol fatty liver disease (NAFLD) and results from a pathological accumulation of fat in the liver. Approximately 5 million people have been diagnosed with NASH in the US alone. NASH can lead to cirrhosis, followed by liver failure or hepatocellular carcinoma. The projected number of diagnosed NASH patients worldwide is about 16 million. The current primary treatment for NASH is lifestyle change. However, few patients remain adherent for extended periods of time. No drugs have been approved in the US or other countries for treating NASH. To address this unmet medical need, we are taking the innovative approach of treating NASH by increasing mitochondrial metabolism in the liver. Fatty acids are transported to the liver where they are metabolized in mitochondria through -oxidation, which is coupled to the electron transport chain (ETC) and mitochondrial respiration. Increasing the activity of the ETC in the liver could therefore speed up the degradation of fatty acids and prevent their accumulation in the liver. A key endogenous negative regulator of the ETC is the MCJ protein (MCJ/DnaJC15 or Methylation-Controlled J protein). MCJ is a mitochondrial protein that acts as a brake on the ETC (“internal mitochondrial brake”). We have demonstrated that removal of MCJ is safe and results in increased mitochondrial respiration without increasing the generation of reactive oxygen species. This is because removal of MCJ minimizes electron leak by promoting the formation of respiratory supercomplexes. In preliminary studies, we used mouse specific siRNAs to show safety of our approach and efficacy for reversal and prevention of pathologies that are associated with NASH, using multiple mouse models of NASH. siRNA has been validated as a drug for a number of diseases, with two siRNA drugs recently approved by FDA for treatment of liver diseases (Patisiran and Givosiran). In addition, GalNAc (N-acetylgalactosamine) has been used clinically to direct siRNA to liver hepatocytes. We have identified a lead siRNA that is cross-reactive for human, NHP, and mouse MCJ. We have also developed proprietary GalNAc vectors and a lead siRNA-GalNAc formulation (MITO-1041), but that formulation has not yet been tested in NASH models or for the rare occurrence of polynucleotide liver toxicity. In Phase I, we will test for toxicity and efficacy. Back-up compounds have also been identified to de-risk the program. Upon success of Phase I, we will apply to the NIH for Phase II funding. In Phase II, we will carry out a number of IND enabling studies, as suggested by NIDDK. Following the success of these studies, we will submit an SBIR Phase IIb proposal to manufacture GMP material, carry out the final GLP tox studies in rat and NHPs, submit an IND, and carry out a first in human Phase I clinical study.