Isoform-Selective AMPK Agonists for Treating Subtypes of Mitochondrial Disease

用于治疗线粒体疾病亚型的异构体选择性 AMPK 激动剂

基本信息

  • 批准号:
    10252080
  • 负责人:
  • 金额:
    $ 35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-01 至 2022-08-31
  • 项目状态:
    已结题

项目摘要

ABSRACT Mitochondrial diseases are a clinically heterogenous group of orphan disorders caused by electron transport chain (ETC) dysfunction and associated with degenerative symptoms affecting single organ or multisystem function. There is no effective treatment or cure and no FDA-approved drug for any of these devastating disorders. To identify and characterize potential therapeutic compounds, we developed an in vitro screening assay and identified direct AMP-activated protein kinase (AMPK) activators originally explored for the treatment of diabetes and metabolic syndrome. Unlike previously investigated AMPK agonists such as 5- Aminoimidazole-4-carboxamide ribonucleotide (AICAR), these compounds allosterically activate AMPK in an AMP-independent manner, thereby increasing specificity and decreasing pleiotropic effects. We showed that direct AMPK activators significantly improve mitochondrial function, energy status, and cellular redox of fibroblasts isolated from patients with mitochondrial disease. We also showed that they protected against retinal degeneration and improved muscle weakness in a mouse model of mitochondrial dysfunction, further supporting the therapeutic potential of direct AMPK agonists in the treatment of mitochondrial diseases. While direct AMPK agonists proved effective in reducing organ damage caused by mitochondrial dysfunction, activating AMPK broadly across tissue also resulted in cardiac hypertrophy. In order to improve tissue selectivity and reduce off-target tissue effects associated with pan-AMPK activation, we developed a class of proprietary AMPK activators that selectively activate AMPK isoforms highly expressed in human eye tissue. These selective agonists will be valuable in treating Leber's Hereditary Optic Neuropathy (LHON), a subtype of mitochondrial disease characterized by severe vision loss that leads to blindness mostly in teens and young adults. We formed Evvia Therapeutics as a result of this promising academic research and now seek to verify the pharmacological safety properties of the proprietary agonists through both in vitro and in vivo ADME-Tox assessments. We also seek to evaluate the efficacy of our agonists using a mouse model of LHON in preparation for IND-enabling studies. 1
摘要 线粒体疾病是由电子传递引起的一组临床异质性孤儿疾病 链(ETC)功能障碍,并伴有影响单个器官或多系统的退行性症状 功能没有有效的治疗或治愈,也没有FDA批准的药物用于这些毁灭性的疾病。 紊乱为了鉴定和表征潜在的治疗化合物,我们开发了一种体外筛选方法, 测定并鉴定了最初用于治疗的直接AMP活化蛋白激酶(AMPK)激活剂 糖尿病和代谢综合征的症状与先前研究的AMPK激动剂如5- 氨基咪唑-4-甲酰胺核糖核苷酸(AICAR),这些化合物在一个细胞中变构激活AMPK。 AMP非依赖性方式,从而增加特异性和减少多效性效应。我们发现 直接AMPK激活剂显著改善线粒体功能、能量状态和细胞氧化还原, 从患有线粒体疾病的患者分离的成纤维细胞。我们还发现, 在线粒体功能障碍的小鼠模型中, 支持直接AMPK激动剂在治疗线粒体疾病中的治疗潜力。而 直接AMPK激动剂被证明有效减少由线粒体功能障碍引起的器官损伤, 在整个组织中广泛激活AMPK也导致心脏肥大。为了改善组织 选择性和减少与泛AMPK激活相关的脱靶组织效应,我们开发了一类 专利AMPK激活剂,选择性激活在人眼组织中高度表达的AMPK亚型。 这些选择性激动剂在治疗Leber遗传性视神经病变(LHON)中将是有价值的,LHON是Leber遗传性视神经病变的一种亚型。 线粒体疾病以严重视力丧失为特征,主要导致青少年失明 成年人了由于这项有前途的学术研究,我们成立了Evvia Therapeutics,现在寻求验证 通过体外和体内ADME-Tox研究专利激动剂的药理学安全性 评估。我们还试图使用LHON小鼠模型评估我们的激动剂在以下方面的功效: 为IND赋能研究做准备。 1

项目成果

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Tereza Moore的其他文献

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