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

治疗非酒精性脂肪性肝炎（NASH）的新方法

• 批准号: 10630832
• 负责人: Cynthia Arbeeny
• 金额: $ 100.9万
• 依托单位: MITOTHERAPEUTIX, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10630832
• 关键词: Acetylgalactosamine; Address; Bioinformatics; Cirrhosis; Clinical; Clinical Research; Country; Coupled; Diabetes Mellitus; Diagnosis; Disease; Disease model; Dose; Electron Transport; Electrons; Excision; FDA approved; Fatty Acids; Fatty acid glycerol esters; Fibrosis; Formulation; Frequencies; Funding; Generations; Goals; Hepatocyte; Hepatotoxicity; Human; Human Cell Line; Hyperlipidemia; In Vitro; Individual; Industry Standard; Inflammation; Lead; Life Style; Liver; Liver Failure; Liver diseases; Medical; Metabolic; Metabolic Diseases; Methylation; Mitochondria; Mitochondrial Proteins; Modeling; Mouse Cell Line; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Nucleotides; Obesity; Oligonucleotides; Pathologic; Pathology; Patients; Persons; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Polynucleotides; Population; Prevention; Primary carcinoma of the liver cells; Proteins; Rationalization; Rattus; Reactive Oxygen Species; Research; Resources; Respiration; Risk; Rodent; Safety; Scientist; Small Business Innovation Research Grant; Small Interfering RNA; Speed; Steatohepatitis; Study Section; Technology; Testing; Therapeutic; Time; Toxic effect; Toxicity Tests; United States National Institutes of Health; commercialization; cost; cross reactivity; design; drug candidate; drug development; drug discovery; experience; fatty acid transport; feasibility testing; first-in-human; human study; in vivo; innovation; knock-down; lipid nanoparticle; manufacture; member; mitochondrial metabolism; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel strategies; oxidation; pre-clinical; prevent; programs; respiratory; risk mitigation; screening; success; vector

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.

抽象的 该 SBIR 快速通道申请的目标是对我们的 siRNA 药物开展多项 IND 研究 候选药物，旨在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）是肝脏脂肪病理性积累的结果。约500万 仅在美国就有人被诊断出患有 NASH。 NASH 可导致肝硬化，进而导致肝功能衰竭或 肝细胞癌。预计全球确诊的 NASH 患者人数约为 1600 万。这 目前 NASH 的主要治疗方法是改变生活方式。然而，很少有患者能够长期坚持治疗。 一段时间。美国或其他国家尚未批准用于治疗 NASH 的药物。 为了解决这一未满足的医疗需求，我们正在采取创新方法来治疗 NASH，增加 肝脏中的线粒体代谢。脂肪酸被运输到肝脏并在那里进行代谢 线粒体通过β-氧化作用，与电子传递链（ETC）和线粒体偶联 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 的一个关键内源性负调节因子是 MCJ 蛋白 （MCJ/DnaJC15 或甲基化控制的 J 蛋白）。 MCJ 是一种线粒体蛋白，可作为刹车 ETC（“线粒体内部制动”）。我们已经证明去除 MCJ 是安全的，并且会导致增加 线粒体呼吸而不增加活性氧的产生。这是因为去除 MCJ 通过促进呼吸超复合物的形成来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 来证明我们方法的安全性和逆转功效 使用多种 NASH 小鼠模型来预防与 NASH 相关的病理。 siRNA 已被验证为治疗多种疾病的药物，其中两种 siRNA 药物最近获得 FDA 批准用于治疗 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。我们已经鉴定出一种具有交叉反应性的先导 siRNA 人类、NHP 和小鼠 MCJ。我们还开发了专有的 GalNAc 载体和先导 siRNA-GalNAc 配方（MITO-1041），但该配方尚未在 NASH 模型中或罕见情况下进行测试 多核苷酸肝毒性。在第一阶段，我们将测试毒性和功效。备用化合物也 已确定可以降低该计划的风险。一旦第一阶段成功，我们将向美国国立卫生研究院申请第二阶段资金。在 第二阶段，我们将按照 NIDDK 的建议开展多项 IND 授权研究。继成功之后 这些研究，我们将提交 SBIR IIb 期提案来生产 GMP 材料，执行最终的 GLP 在大鼠和 NHP 中进行毒性研究，提交 IND，并开展首次人体 I 期临床研究。