Targeting novel translation mechanism to treat NFOO-induced hypoxia-related brain injuries

About This Grant

Project Summary Opioid misuse remains an unrelenting epidemic, and, while widespread use of naloxone saves lives by acutely reversing the short-term effects of opioid overdose, therapeutic options for mitigating the debilitating complications from non-fatal opioid overdose (NFOO) are entirely lacking. Respiratory suppression and subsequent hypoxia are the primary causes of adverse health effects seen in NFOO, which include kidney failure, heart complications, seizures, nerve damage, and particularly brain injury resulting in impaired cognitive, affective, and motor function. Evidently, the histone methyltransferase G9a is a key mediator of hypoxia-induced damage in tissues by suppressing genes critical to protecting against oxidative damage, fibrosis, inflammation, and apoptosis. Specifically, animal studies demonstrate G9a inhibition to be protective in many hypoxia models, including stroke, myocardial infarction, and ischemia/reperfusion, implicating the mechanistic role of G9a activity in NFOO-induced hypoxia-related pathogenesis. Recently, we made a breakthrough discovery identifying a G9a- mediated translation mechanism driving neuropathogenesis in Alzheimer’s Disease (AD). Based on this mechanistic discovery we developed and characterized MS1262, a novel, potent, brain-penetrant inhibitor of G9a, as an effective drug for AD therapeutics. Here, by targeting G9a and G9a-mediated translation mechanisms we will develop a similar therapeutics strategy for improving NFOO health outcomes. TransChromix, a startup company created by the NC Kick-Start program, and Professor Xian Chen at the UNC School of Medicine, will conduct this project. MS1262 treatment in three different AD mouse models rescues cognitive and affective function, as well as improves neuroinflammation and synaptic dysfunction, which are hallmarks of brain injury seen in NFOO. Notably, no adverse effects have been observed in these models. Strikingly, in our comparative proteomic and phosphoproteomic analysis of hippocampi from mice receiving acute fentanyl injection with versus without MS1262 treatment, we found that G9a inhibition broadly affected a series of the pathways related to hypoxia- impaired synaptic function and neuronal damage. Using two models of hypoxic stress, including fentanyl injection and hypobaric chambers, we will test the hypothesis that MS1262 treatment will (1) Mitigate hypoxia induced tissue damage and (2) Prevent cognitive, affective, and motor impairments. Furthermore, we will use our state- of-the-art multiomics approaches to identify mouse-to-human conserved mechanisms of NFOO complications rescued by MS1262, thus mechanistically deriving new biomarkers for companion diagnosis of treatment effects that having promising human potential. In Phase II we will use the Phase I-optimized doses with low toxicity to test the treatment efficacy for NFOO complications. Meanwhile, we will develop companion diagnostic assays to stratify individuals for enhanced therapy with high response rates. The end deliverable of phase II funding will be an FDA IND application.