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Reactive oxygen species (ROS) as Elixirs against chronic Disease: OXidative regulatory mechanisms In T cells and neutrophils.

Periodic Reporting for period 2 - REDOXIT (Reactive oxygen species (ROS) as Elixirs against chronic Disease: OXidative regulatory mechanisms In T cells and neutrophils.)

Reporting period: 2017-07-01 to 2019-06-30

REDOXIT 2015-2019

Within our four-year programme of knowledge transfer and networking between University of Surrey (SURREY, UK), Aston University (ASTON, UK), Erlangen Universitat (FAU, Germany) and Redoxis AB (Redoxis, Sweden), we have targeted an emerging area of biology; the role of reactive oxygen species (ROS) in the regulation of immune responses and age-associated inflammatory conditions; we applied small molecule candidate drugs to generate ROS and used innovative approaches for biomarker identification in models of chronic immune disease. This research has significant potential for application in human health and is of particular relevance to the ageing population.

The number of people in the European workforce aged between 55-64 will increase by one third in the next 20 years, growing from 15% to 20%. The number of work days lost by people in this age with rheumatoid arthritis alone represents 20% of all absences. It is therefore important to identify cost-effective treatments that improve the well-being of older people with chronic inflammatory disease and to enable their continued participation in working economy. Our goal was to develop new compounds, explore their potency and protect emerging IP, to grow the economic position of the SME and develop researchers.

The knowledge economy is one of Europe's leading strengths. To grow this capability we need to promote the exchange of ideas. Through the RISE scheme we have successfully delivered training, knowledge transfer and skills exchange between partners and early career researchers. The challenges that we are addressed were balanced between industrial application and basic science, with a focus on knowledge transfer and drug re-purposing.

We conclude that;

1. Novel NOX2 activators are potent inflammatory modulators in primary immune cells.
2. Novel NOX2 activators are effective in disease management in animal models of autoimmune disease.
3. The downstream pathways of NOX2 activator effects on T cells predominantly feature calcium channels.
4. ROS regulate T cell- and neutrophil inflammatory activity.
5. A strengthened academic-industrial relationship has been achieved that has led to a further collaborative project starting in 2020, NeutroCure, that will develop and apply a new class of ROS generators for chronic autoimmune disease. Early career researcher skills have been advanced through embedding new skills, expertise and knowledge transfer in individuals and the collaborator organisations.
6. Innovations have been disseminated within Europe through presentations and worldwide through publications
Throughout the course of the project, seven researchers have exchanged from laboratories in the UK and Germany for 23 months into Redoxis in Sweden and one researcher has exchanged from Sweden into Germany for one month. Researchers have received technical and professional training that has supported career development. The exchanges were designed to coincide as far as possible so that at least three partners were represented during exchanges where-ever possible. During this time, we have made progress against all objectives in the proposal and a summary of the outcomes for each objective is listed below.

1. To explore the potency of novel NOX2 activators in primary immune cells - published article in JCI Insights.

2. To evaluate novel NOX2 activators in animal models of autoimmune disease - as above, published in JCI Insights and for objective 3. Further progress was limited latterly by a change in company direction away from design and synthesis of new drugs, so this work was not progressed further.

3. To investigate the downstream pathways of NOX2 activator effects in target cells - this work was completed and a paper is in revision describing calcium channel target proteins.

4. To describe the T cell- and neutrophil-regulating role of ROS - published in the JCI Insights paper and a second paper has been submitted for publication describing changes in surface expression of peroxi- and thio-redoxins (Prx1 and Trx1 respectively).

5. To strengthen the academic-industrial relationship and enhance early career researcher skills through embedding new skills, expertise and knowledge in individuals and the collaborator organisations - completed. Four PhDs and one MSc have been awarded and researcher destinations are in further study and industry. The collaborator organisations have now been awarded another grant entitled NeutroCure which seeks to exploit new knowledge about ROS generation in neutrophils for autoimmune and orphan diseases.

6. To disseminate innovations within Europe and worldwide - the outcomes of the research have been disseminated in scientific publications and in several conference presentations in Greece, Hungary, Italy, Sweden, Germany, UK and Portugal. Our seminal review, the dual role of Reactive Oxygen Species in autoimmune and inflammatory diseases: evidence from preclinical models, that was published in Free Radical Biology and Medicine during September 2018 has attracted 20 citations in less than a year. A public engagement lecture at the Surrey Health Ageing Research Partnership meeting in September 2018 attracted more than 50 members of the public with interests in the management of age-related disease.
The hypothesis that ROS inducers operating via NOX2 could have therapeutic potential as anti-inflammatory drugs through controlling inflammatory T-cells and neutrophils has opened up a multitude of technological and innovative research challenges. Through this project, we brought together academics who are engaged in the mechanistic (SURREY, ASTON) and pre-clinical evaluation (FAU) of immune responses together with an SME (Redoxis), to collectively address an exciting area of biology that is poorly understood. The SME, Redoxis, has developed a new therapeutic NOX2 activation platform with potential for controlling immune and inflammatory responses, which become dysregulated during specific autoimmune diseases and more generally during ageing. For the first time, and directly due to this project, we have shown that specific chemical NOX2 activators can induce NET formation and ameliorate an experimental chronic inflammatory condition, pristane-induced lupus, in mice. These findings suggest that NOX2-induced NETs can have a protective role against the development of certain forms of lupus.

By capitalising on our combined European leadership in this field through this project, we have demonstrated the potential to deliver innovative new ROS-inducing drugs, which target NOX2 activation. These have potential societal benefit in the future should they be successful in clinical trials. Further progress towards applying this concept of ROS generation through NOX2 activation has potential for application to a broader range of disease conditions.

Impact has been achieved to date through through dissemination and training within scientific professional bodies and at conferences for scientists and the general public. Our recently awarded FET grant, due to start in 2020, NeutroCure, will bring the ROS-production concept to maturity in a range of disease conditions and to explore the potential for new IP and associated socio-economic benefits.
NOX2 activator inhibits immune complex deposition in lupus model