Isoform-Selective AMPK Agonists for Treating Subtypes of Mitochondrial Disease

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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