Isoform-Selective AMPK Agonists for Treating Subtypes of Mitochondrial Disease

抽奖 线粒体疾病是由电子传递引起的一组临床上异质性的孤儿疾病 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方法，也没有FDA批准的药物来治疗这些毁灭性的疾病 精神错乱。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 检测和鉴定最初探索用于治疗的直接AMP激活蛋白激酶(AMPK)激活剂 糖尿病和代谢综合征。与之前研究的AMPK激动剂不同，如5- 氨基咪唑-4-甲酰胺核糖核苷酸(AICAR)，这些化合物变构激活AMPK。 AMP不依赖的方式，从而增加特异性和减少多效性的影响。我们向大家展示了 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 分离自线粒体疾病患者的成纤维细胞。我们还表明，它们能够保护人体免受 线粒体功能障碍小鼠模型的视网膜变性和改善的肌肉无力，进一步 支持直接AMPK激动剂在治疗线粒体疾病方面的治疗潜力。而当 直接AMPK激动剂被证明在减少线粒体功能障碍引起的器官损伤方面有效， 在组织中广泛激活AMPK也会导致心肌肥厚。为了改善组织 为了选择性和减少与PAN-AMPK激活相关的非靶点组织效应，我们开发了一类 专有的AMPK激活剂，选择性地激活在人眼组织中高表达的AMPK亚型。 这些选择性激动剂将在治疗Leber遗传性视神经病变(LHON)方面有价值，LHON是 线粒体疾病，特征是严重的视力丧失，导致失明，主要发生在青少年和年轻人 成年人。作为这项有前景的学术研究的结果，我们成立了Evvia Treeutics，现在寻求验证 专有激动剂的体内外药理安全性研究 评估。我们还试图使用LHON的小鼠模型评估我们的激动剂的疗效。 为支持IND的研究做准备。 1

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