Novel Treatment for Alcohol-associated Liver Disease

酒精相关性肝病的新疗法

基本信息

  • 批准号:
    10698605
  • 负责人:
  • 金额:
    $ 27.39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-04-01 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

Abstract The Specific Aim of this Phase I TTR proposal is to test the feasibility of our siRNA drug to ameliorate the pathology and progression of alcohol-associated liver disease (ALD). Alcohol consumption remains a leading cause of hepatic pathology worldwide and is one of the greatest sources of preventable morbidity and mortality. In the U.S., alcohol abuse impacts over 10 million individuals and is a major healthcare burden. The underlying cause of ALD is multi-factorial, including obesity, oxidative stress, and inflammation, all of which contribute the pathological progression from steatosis to steatohepatitis, cirrhosis, and fibrosis. Effective therapeutic modalities targeting ALD remain critically absent. Targeting the underlying pathological mechanisms leading to alcohol-induced hepatic steatosis may prevent the cascade of events inducing inflammation and irreversible liver damage. Alcohol-induced mitochondrial dysfunction is a key driver of steatosis and related metabolic defects leading to severe ALD. We propose the novel approach of treating ALD by safely increasing mitochondrial metabolism in the liver and will test this in acute and chronic models of ALD. Lipids are transported to the liver where they are metabolized in mitochondria through cytosolic beta-oxidation, which is coupled through the citric acid cycle to the electron transport chain (ETC) and mitochondrial respiration. NADH and FADH2, are the two main products from beta-oxidation that feed into the ETC (NADH is substrate for Complex I and FADH2 for Complex II), therefore increasing ETC activity will increase beta- oxidation. Enhancing hepatic ETC activity could therefore speed up the degradation of fatty acids, preventing steatosis. 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 negatively regulates ETC metabolism by binding to complex I. Our work demonstrates that removal of MCJ appears to be safe and increases mitochondrial respiration without inducing oxidative stress. We have developed a GalNAc (N-acetylgalactosamine) linked siRNA drug that is specific to MCJ. Conjugation to GalNAc directs the siRNA to liver hepatocytes and provides a direct route targeting ALD. Validating an siRNA approach to treating liver disease, two GalNAc linked siRNA drugs are approved by the FDA for treatment of liver diseases (Patisiran, lipid-nanoparticle formulated siRNA and Givosiran, GalNAc-conjugated siRNA). We have developed a lead therapeutic, GalNAc linked siRNA specific to MCJ (MITO-1041) and validated our siRNA approach to reducing steatosis and fibrosis in liver using many mouse models of fatty liver disease. MITO-1041 is proprietary and specific for human, primate, and mouse MCJ, allowing for rapid IND enabling studies when the time comes. However, we have not yet tested MITO-1041 in mouse models of ALD. Therefore, our Specific Aim of this project is to test the feasibility of using a hepatic MCJ targeted siRNA (MITO-1041) to ameliorate alcohol-induced steatosis and associated pathologies.
摘要 该I期TTR提案的具体目的是测试我们的siRNA药物改善肿瘤细胞增殖的可行性。 酒精相关性肝病(ALD)的病理学和进展。酒精消费仍然是主要的 是世界范围内肝脏病理学的主要原因,也是可预防疾病的最大来源之一, mortality.在美国,酒精滥用影响了1000多万人,是一个主要的医疗负担。的 ALD的根本原因是多因素的,包括肥胖、氧化应激和炎症,所有这些因素都 导致从脂肪变性到脂肪性肝炎、肝硬化和纤维化的病理进展。 有效的治疗方式针对ALD仍然严重缺乏。针对潜在的病理 导致酒精诱导的肝脂肪变性的机制可能会阻止诱导肝脂肪变性的级联反应。 炎症和不可逆的肝损伤。酒精诱导的线粒体功能障碍是一个关键的驱动因素, 脂肪变性和相关代谢缺陷导致严重ALD。我们提出了治疗ALD的新方法 通过安全地增加肝脏中的线粒体代谢,并将在ALD的急性和慢性模型中测试这一点。 脂质被转运到肝脏,在那里它们在线粒体中通过细胞溶质β-氧化代谢, 其通过柠檬酸循环与电子传递链(ETC)和线粒体偶联 呼吸NADH和FADH 2是进入ETC的来自β-氧化的两种主要产物(NADH是 复合物I的底物和复合物II的FADH 2),因此增加ETC活性将增加β- 氧化因此,增强肝脏ETC活性可以加速脂肪酸的降解, 脂肪变性ETC的关键内源性负调节因子是MCJ蛋白(MCJ/DnaJC 15或甲基化- 受控J蛋白)。MCJ是一种线粒体蛋白,其通过结合至 复合体I我们的工作表明,去除MCJ似乎是安全的,并增加线粒体 呼吸而不引起氧化应激。我们已经开发了一种GalNAc(N-乙酰半乳糖胺)连接 特异性针对MCJ的siRNA药物。与GalNAc的缀合将siRNA引导至肝细胞,并提供 一条直接针对酒精中毒的路线验证siRNA治疗肝病的方法,两种GalNAc连接的siRNA FDA批准药物用于治疗肝病(Patisiran,脂质纳米颗粒配制的siRNA 和Givosiran,GalNAc缀合的siRNA)。 我们已经开发了一种领先的治疗剂,GalNAc连接的特异于MCJ的siRNA(MITO-1041),并验证了我们的研究。 使用许多脂肪肝病小鼠模型的siRNA方法减少肝脏中的脂肪变性和纤维化。 MITO-1041是人类、灵长类动物和小鼠MCJ的专有和特异性药物,允许快速IND启用 到时候再学习。然而,我们尚未在ALD小鼠模型中测试MITO-1041。 因此,我们本项目的具体目的是测试使用肝MCJ靶向siRNA的可行性, (MITO-1041)以改善酒精诱导的脂肪变性和相关病理。

项目成果

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Kristofer S. Fritz其他文献

Profiling Protein Carbonylation in a Murine Model of Alcoholic Liver Disease
  • DOI:
    10.1016/j.freeradbiomed.2011.10.046
  • 发表时间:
    2011-11-01
  • 期刊:
  • 影响因子:
  • 作者:
    James J. Galligan;Kristofer S. Fritz;Rebecca L. Smathers;Dennis R. Petersen
  • 通讯作者:
    Dennis R. Petersen
Acetylation of proximal cysteine-lysine pairs by alcohol metabolism
酒精代谢导致近端半胱氨酸 - 赖氨酸对的乙酰化
  • DOI:
    10.1016/j.redox.2024.103462
  • 发表时间:
    2025-02-01
  • 期刊:
  • 影响因子:
    11.900
  • 作者:
    Courtney D. McGinnis;Peter S. Harris;Brenton I.M. Graham;John O. Marentette;Cole R. Michel;Laura M. Saba;Richard Reisdorph;James R. Roede;Kristofer S. Fritz
  • 通讯作者:
    Kristofer S. Fritz
Modulation of the thiol redox proteome by sugarcane ash-derived silica nanoparticles: Insights into chronic kidney disease of unknown etiology
甘蔗灰衍生二氧化硅纳米粒子对硫醇氧化还原蛋白质组的调节:对病因不明的慢性肾脏病的见解
  • DOI:
    10.1016/j.freeradbiomed.2025.05.158
  • 发表时间:
    2025-06-01
  • 期刊:
  • 影响因子:
    8.200
  • 作者:
    Arthur D. Stem;Cole R. Michel;Peter S. Harris;Keegan L. Rogers;Matthew Gibb;Carlos A. Roncal-Jimenez;Richard Reisdorph;Richard J. Johnson;James R. Roede;Kristofer S. Fritz;Jared M. Brown
  • 通讯作者:
    Jared M. Brown
Mitochondrial Acetylomic Analysis in a Mouse Model of Alcohol-Induced Liver Injury Utilizing SIRT3 Knockout Mice
  • DOI:
    10.1016/j.freeradbiomed.2011.10.044
  • 发表时间:
    2011-11-01
  • 期刊:
  • 影响因子:
  • 作者:
    Kristofer S. Fritz;James J. Galligan;Matthew D. Hirschey;Eric Verdin;Dennis R. Petersen
  • 通讯作者:
    Dennis R. Petersen

Kristofer S. Fritz的其他文献

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{{ truncateString('Kristofer S. Fritz', 18)}}的其他基金

Alcohol Metabolism Disrupts Hepatic Thiol Redox Signaling and Control
酒精代谢破坏肝脏硫醇氧化还原信号和控制
  • 批准号:
    10585786
  • 财政年份:
    2023
  • 资助金额:
    $ 27.39万
  • 项目类别:
Mechanisms of Alcohol Toxicity and Kidney Damage
酒精中毒和肾脏损害的机制
  • 批准号:
    10371787
  • 财政年份:
    2021
  • 资助金额:
    $ 27.39万
  • 项目类别:
Mechanisms of Alcohol Toxicity and Kidney Damage
酒精中毒和肾脏损害的机制
  • 批准号:
    10493371
  • 财政年份:
    2021
  • 资助金额:
    $ 27.39万
  • 项目类别:
Regulation of insulin signaling and sensitivity by the xenobiotic metabolizing enzyme NQO1
异生物质代谢酶 NQO1 对胰岛素信号传导和敏感性的调节
  • 批准号:
    9905510
  • 财政年份:
    2017
  • 资助金额:
    $ 27.39万
  • 项目类别:
Regulation of insulin signaling and sensitivity by the xenobiotic metabolizing enzyme NQO1
异生物质代谢酶 NQO1 对胰岛素信号传导和敏感性的调节
  • 批准号:
    9309955
  • 财政年份:
    2017
  • 资助金额:
    $ 27.39万
  • 项目类别:
Ethanol-induced Protein Acylation Regulates Metabolism
乙醇诱导的蛋白质酰化调节代谢
  • 批准号:
    8712307
  • 财政年份:
    2013
  • 资助金额:
    $ 27.39万
  • 项目类别:
Ethanol-induced Protein Acylation Regulates Metabolism
乙醇诱导的蛋白质酰化调节代谢
  • 批准号:
    8482109
  • 财政年份:
    2013
  • 资助金额:
    $ 27.39万
  • 项目类别:
Ethanol-induced Protein Acylation Regulates Metabolism
乙醇诱导的蛋白质酰化调节代谢
  • 批准号:
    9297179
  • 财政年份:
    2013
  • 资助金额:
    $ 27.39万
  • 项目类别:
Ethanol-induced Protein Acylation Regulates Metabolism
乙醇诱导的蛋白质酰化调节代谢
  • 批准号:
    9087076
  • 财政年份:
    2013
  • 资助金额:
    $ 27.39万
  • 项目类别:
Ethanol-induced Protein Acylation Regulates Metabolism
乙醇诱导的蛋白质酰化调节代谢
  • 批准号:
    8867963
  • 财政年份:
    2013
  • 资助金额:
    $ 27.39万
  • 项目类别:

相似国自然基金

SirT1在Acetaminophen诱发的药物性肝损伤中的作用及机制
  • 批准号:
    81100281
  • 批准年份:
    2011
  • 资助金额:
    24.0 万元
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Diverging roles of EGFR and MET in acetaminophen-induced acute liver injury
EGFR 和 MET 在对乙酰氨基酚诱导的急性肝损伤中的不同作用
  • 批准号:
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  • 财政年份:
    2023
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对乙酰氨基酚和抗坏血酸脓毒症试验中器官功能障碍和恢复的机制
  • 批准号:
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Mechanisms of organ dysfunction and recovery in the Acetaminophen and Ascorbate Trial in Sepsis
对乙酰氨基酚和抗坏血酸脓毒症试验中器官功能障碍和恢复的机制
  • 批准号:
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Pulmonary implications of perinatal acetaminophen exposure
围产期对乙酰氨基酚暴露对肺部的影响
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心脏手术后静脉注射对乙酰氨基酚 (IVACS)
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围产期对乙酰氨基酚暴露对肺部的影响
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