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

摘要 这项SBIR快速通道申请的目标是对我们的siRNA药物进行大量IND研究 候选人，旨在治疗非酒精性脂肪性肝炎（NASH）。NASH是一种非酒精脂肪酸形式， 肝脏疾病（NAFLD）是由肝脏中脂肪的病理性积累引起的。约5百万 仅在美国就有人被诊断出患有NASH。NASH可导致肝硬化，随后是肝衰竭或 肝细胞癌预计全球确诊的NASH患者人数约为1600万。的 目前NASH的主要治疗是改变生活方式。然而，很少有患者保持长期的依从性。 一段时间。在美国或其他国家，没有药物被批准用于治疗NASH。 为了解决这一未满足的医疗需求，我们正在采取创新的方法治疗NASH， 肝脏中的线粒体代谢。脂肪酸被转运到肝脏，在肝脏中代谢， 线粒体通过？氧化，这是耦合到电子传递链（ETC）和线粒体 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累。ETC的关键内源性负调节因子是MCJ蛋白 (MCJ/DnaJC 15或甲基化控制的J蛋白）。MCJ是一种线粒体蛋白质，它在细胞内起着刹车的作用。 ETC（“内部线粒体制动”）。我们已经证明，去除MCJ是安全的， 线粒体呼吸而不增加活性氧的产生。这是因为， MCJ通过促进呼吸超复合物的形成而使电子泄漏最小化。 在初步研究中，我们使用小鼠特异性siRNA来显示我们的方法的安全性和逆转的有效性。 和预防与NASH相关的病理。siRNA 已经被验证为用于许多疾病的药物，其中两种siRNA药物最近被FDA批准用于 治疗肝脏疾病（Patisiran和Givosiran）。此外，GalNAc（N-乙酰半乳糖胺）已被 临床上用于将siRNA引导至肝细胞。我们已经鉴定了一种前导siRNA，其与以下蛋白交叉反应： 人、NHP和小鼠MCJ。我们还开发了专有的GalNAc载体和领先的siRNA-GalNAc 制剂（MITO-1041），但该制剂尚未在NASH模型中进行测试或用于罕见事件 多核苷酸肝毒性。在第一阶段，我们将测试毒性和疗效。备用化合物也 已被确定为消除该计划的风险。在第一阶段成功后，我们将向NIH申请第二阶段的资助。在 在第二阶段，我们将按照NIDDK的建议开展一些IND赋能研究。获得成功后 在这些研究中，我们将提交SBIR IIb期提案，以生产GMP材料，执行最终GLP 在大鼠和NHP中进行毒性研究，提交IND，并进行首次人体I期临床研究。

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.