Attempts to develop drug treatments for acute stroke have not fulfilled expectations. Perhaps best illustrating this unsatisfactory situation is the hisory of therapeutic strategies directed at the inhibition of reactive oxygen species (ROS). While decades of laboratory and clinical studies make it clear that ROS are pathogenically important across the entire spectrum of cerebrovascular disease, as well as many other disorders, the beneficial effects of anti-oxidants in clinical trials for stroke have been unimpressive. These negative outcomes may be attributed in part to the heterogeneous nature of cerebral ischemia, which tends to obfuscate the design and interpretation of clinical trials. There also remains considerable scientific uncertainty about the molecular targets of anti-oxidant drug action. For example, non-selective antioxidants may disrupt signaling required for cell survival and recovery. The strategies currently available may not target the key sentinel molecule(s) that integrate the cellular effects of ROS and ROS signaling. Mitochondrial DNA (mtDNA) is far more sensitive to oxidative damage than the nuclear genome. Further, multiple lines of evidence support the idea that mtDNA serves as a molecular sentinel controlling cell fate in response to oxidant stress. There is also a conspicuous association between mtDNA damage and oxidant- induced cell death: the propensity for cytotoxicity is inversely related to the efficiency of mtDNA repair. We have shown this relationship in ischemic brain. Moreover, it has been found that in the nervous system, 8- oxoguanine DNA glycosylase (Ogg1), the first enzyme in base excision repair, is neuroprotective in the setting of oxidative DNA damage in vitro and in modeled stroke in vivo. Based on these provocative findings, the small business concern, Exscien, and its university partners devised and patented novel fusion protein constructs targeting DNA repair glycosylases to mitochondria and demonstrated in clinically-relevant rodent models that the new agents exert no off-target effects and suppress injury in several models of organ transplantation. We now propose to verify the efficacy of mitochondria-targeted DNA repair """"""""drugs"""""""" in a different type of ischemia- reperfusion injury, namely stroke. The intent of this Phase I proposal is to establish proof-of-concept that pharmacologic enhancement of mtDNA repair attenuates the degree of brain infarction following reperfusion. This proposed application is innovative because it will herald first-in-class, platform molecules directed against a novel target in stroke, mtDNA, and many other disorders where oxidant stress plays a pathogenic role.
There are currently limited pharmacologic interventions to treat stroke. In a related context, while reactive oxygen species play a role in these disorders, non-selective anti-oxidants have proven ineffective. Herein, we will test a new concept - that repair of oxidative mtDNA damage directs cell fate decisions in stroke, which if valid, will point o an entirely new pharmacologic strategy for treating stroke and related disorders.
