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Free Radical Pharmacology: Generators, Targets and Therapeutic Implications

Final Report Summary - RADICAL PHARMACOLOGY (Free Radical Pharmacology: Generators, Targets and Therapeutic Implications)

Life with oxygen comes at the expense of the formation of so-called reactive oxygen species that can cause harm in the body but are also used as signalling molecules. NO radicals are generally protective, superoxide antagonises NO and thus can cause disease. Innovative, mechanism-based and personalised therapies are based on (a) inhibiting oxygen radical formation (from NADPH oxidase, NOX), or (b) augmenting protective NO synthesis (by re-coupling NO synthase or re-activating the oxidatively damaged NO receptor, soluble guanylate cyclase (SGC).

This project aimed and achieved to establish and validate these new approaches and to co-develop matching diagnostics. My team identified NOX4 and NOX5 as novel, mechanism-based therapeutic targets for ischemic stroke and diabetic nephropathy; NOX1, in diabetic atherosclerosis and retinopathy. Here inhibitory drugs proved to be beneficial and this principle is now co-developed with a Swedish biotech company for clinical development. Also a detrimental role for high levels of NO and potentiation with ROS was found suggesting a possible combination therapy. Moreover, on the beneficial side, sGC, the NO receptor was found to be reduced in stroke and could be activated by e new compound class, now also in clinical development. This also reduced stroke size suggesting even a triple therapy may be possible.

These activities were scaled up to two major European networks as COST actions on NO (ENOG) and ROS (EU-ROS) as well as an Advanced Grant (RadMed), a EUROSTARS drug development programme and a H2020 application on ROS as a common mechanism explaining several comorbidities (COMMOX in PHC-03).

Collectively, we achieved transfer of our research from Australia to Europe and scientific breakthroughs towards an entirely new approach to “oxidative stress” with high socio-economically relevant impact. We look forward taking this now to direct patient benefit.