Redoxis AB

Lund, Sweden

Redoxis AB

Lund, Sweden

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Grant
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-2.4.5-12 | Award Amount: 14.81M | Year: 2008

Objective: To delineate the biological and molecular pathways that initiate and drive chronic inflammatory disease and to transform the knowledge obtained into the development of novel anti-inflammatory interventions. Focus will be given to Rheumatoid Arthritis (RA) since longitudinal data indicate that intensive treatment can prevent persistency and chronicity. State of the Art and beyond: The first generation of targeted therapies in chronic inflammatory disease used RA as prototype disease for clinical development. These therapies are now also used in other inflammatory disorders. Although treatments have been developed that are effective in a proportion of patients, they are aspecific, relatively toxic and do not mediate cure. Currently, it is unknown which molecular effects need to be induced and/or targeted to prevent induction or persistency of RA. However, this is within reach through a strong international consortium of world-leading European groups that cover both basic- and translational research. Work plan: The general strategy for the project is to enable parallel studies that are focussed on critical switch moments in the biological processes that drive chronicity of inflammation. As the consortium consists of a multidisciplinary team with basic- and clinical expertise, translational research will be conducted to delineate the molecular basis of dysregulated inflammation, the RA-specific autoimmune-response and organ specific pathobiology. The final aim is to develop novel- and specific anti-inflammatory therapies. Impact of the project: This project will (i) identify the molecular networks underlying chronic inflammation and thereby (ii) will define novel targets for drug-development as well as (iii) algorithms that will predict outcome of therapy. Moreover, within this project European SMEs will evaluate new interventions (iv) and this project will (v) offer a platform to rapidly develop ideas and patents into new therapies.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2011.2.2.1-2 | Award Amount: 17.04M | Year: 2012

NEURINOX aims at elucidating the role of NADPH oxidases (NOX) in neuroinflammation and its progression to neurodegenerative diseases (ND), as well as evaluating the potential of novel ND therapeutics approaches targeting NOX activity. NOX generate reactive oxygen species (ROS) and have emerged as regulators of neuroinflammation. Their role is complex: ROS generated by NOX lead to tissue damage in microglia-mediated neuroinflammation, as seen in amyotrophic lateral sclerosis (ALS), while absence of ROS generation enhances the severity of autoimmune-mediated neuroinflammation, as seen for e.g. in multiple sclerosis (MS). The objective of the 5 years NEURINOX project is to understand how NOX controls neuroinflammation, identify novel molecular pathways and oxidative biomarkers involved in NOX-dependent neuroinflammation, and develop specific therapies based on NOX modulation. The scientific approach will be to: (i) identify NOX-dependent molecular mechanisms using dedicated ND animal models (ii) develop therapeutic small molecules either inhibiting or activating NOX and test their effects in animal models (iii) test the validity of identified molecular pathways in clinical studies in ALS and MS patients. NEURINOX will contribute to better understand brain dysfunction, and more particularly the link between neuroinflammation and ND and to identify new therapeutic targets for ND. A successful demonstration of the benefits of NOX modulating drugs in ALS and MS animal models, and in ALS early clinical trials will validate a novel high potential therapeutics target for ALS and also many types of ND. NEURINOX has hence a strong potential for more efficient ND healthcare for patients and thus for reducing ND healthcare costs. This multi-disciplinary consortium includes leading scientists in NOX research, ROS biology, drug development SMEs, experts in the neuroinflammatory aspects of ND, genomics and proteomics, and clinicians able to translate the basic science to the patient.


Sareila O.,University of Turku | Jaakkola N.,University of Turku | Olofsson P.,Redoxis AB | Kelkka T.,University of Turku | And 2 more authors.
Journal of Leukocyte Biology | Year: 2013

A point mutation in the mouse Ncf1m1J gene decreases production of ROS by the phagocytic NOX2 complex. Three mRNA splice variants are expressed, but only one is expressed as a protein, although at lower levels than the WT NCF1 (also known as p47phox). Our aim was to investigate whether the mutant p47phox, lacking 8 aa, is active, but as a result of its low expression, ROS production is decreased in Ncf1m1J mice, or whether the mutant p47phox completely lacks the capability to activate the NOX2 complex. The p47phox mutant (Δ228-235), which was equal to the protein in Ncf1m1J mice, failed to activate the NOX2 complex. When the deleted region was narrowed down to 2 aa, the p47phox protein remained inactive and failed to translocate to the membrane upon activation. Single amino acid substitutions revealed Thr233 to be vital for ROS production. Residues Tyr231 and Val232 also seemed to be important for p47phox function, as p47phox_Y231G and p47phox_V232G resulted in a >50% decrease in ROS production by the NOX2 complex. In addition, we identified the epitope of the D-10 anti-p47phox mAb. In conclusion, the p47phox protein variant expressed in Ncf1m1J mice is completely defective in activating the NOX2 complex to produce ROS, and the effect is dependent on SH3 region amino acids at positions 231-233, which are vital for the proper assembly of the NOX2 complex. © Society for Leukocyte Biology.


Hultqvist M.,Lund University | Hultqvist M.,Redoxis AB | Sareila O.,University of Turku | Vilhardt F.,Copenhagen University | And 7 more authors.
Antioxidants and Redox Signaling | Year: 2011

The Ncf1 gene, encoding the P47 PHOX protein that regulates production of reactive oxygen species (ROS) by the phagocyte NADPH oxidase (NOX2) complex, is associated with autoimmunity and arthritis severity in rats. We have now identified that the single-nucleotide polymorphism (SNP) resulting in an M153T amino acid substitution mediates arthritis resistance and thus explains the molecular polymorphism underlying the earlier identified Ncf1 gene effect. We identified the SNP in position 153 to regulate ROS production using COS PHOX cells transfected with mutated Ncf1. To determine the role of this SNP for control of arthritis, we used the Wistar strain, identified to carry only the postulated arthritis resistant SNP in position 153. When this Ncf1 allele was backcrossed to the arthritis susceptible DA strain, both granulocyte ROS production and arthritis resistance were restored. Position 153 is located in the hinge region between the PX and SH3 domains of P47 PHOX. Mutational analysis of this position revealed a need for an -OH group in the side chain but we found no evidence for phosphorylation. The polymorphism did not affect assembly of the P47 PHOX/P67 PHOX complex in the cytosol or membrane localization, but is likely to operate downstream of assembly, affecting activity of the membrane NOX2 complex. © 2011 Mary Ann Liebert, Inc.


Sareila O.,University of Turku | Kelkka T.,University of Turku | Kelkka T.,Karolinska Institutet | Pizzolla A.,Karolinska Institutet | And 3 more authors.
Antioxidants and Redox Signaling | Year: 2011

Reactive oxygen species (ROS) are a heterogeneous group of highly reactive molecules that oxidize targets in a biologic system. During steady-state conditions, ROS are constantly produced in the electron-transport chain during cellular respiration and by various constitutively active oxidases. ROS production can also be induced by activation of the phagocyte NADPH oxidase 2 (NOX2) complex in a process generally referred to as an oxidative burst. The induced ROS have long been considered proinflammatory, causing cell and tissue destruction. Recent findings have challenged this inflammatory role of ROS, and today, ROS are also known to regulate immune responses and cell proliferation and to determine T-cell autoreactivity. NOX2-derived ROS have been shown to suppress antigen-dependent T-cell reactivity and remarkably to reduce the severity of experimental arthritis in both rats and mice. In this review, we discuss the role of ROS and the NOX2 complex as suppressors of autoimmunity, inflammation, and arthritis. © 2011 Mary Ann Liebert, Inc.


Griffiths H.R.,Aston University | Bennett S.J.,Aston University | Olofsson P.,Redoxis AB | Dunston C.R.,Aston University
Biochemical Society Transactions | Year: 2014

The oxidoreductase Trx-1 (thioredoxin 1) is highly conserved and found intra- and extra-cellularly in mammalian systems. There is increasing interest in its capacity to regulate immune function based on observations of altered distribution and expression during ageing and disease. We have investigated previously whether extracellular T-cell or peripheral blood mononuclear cell Trx-1 levels serve as a robust marker of ageing. In a preliminary study of healthy older adults compared with younger adults, we showed that therewas a significant, butweak, relationshipwith age. Interestingly, patientswith rheumatoid arthritis and cancer have been described by others to secrete or express greater surface Trx-1 than predicted. It is interesting to speculate whether a decline in Trx-1 during ageing protects against such conditions, but correspondingly increases risk of disease associated with Trx-1 depletion such as cardiovascular disease. These hypotheses are being explored in the MARK-AGE study, and preliminary findings confirm an inverse correlation of surface Trx-1 with age. We review recent concepts around the role of Trx-1 and its partners in T-cell function on the cell surface and as an extracellular regulator of redox state in a secreted form. Further studies on the redox state and binding partners of surface and secreted Trx-1 in larger patient datasets are needed to improve our understanding of why Trx-1 is important for lifespan and immune function. © The Authors Journal compilation © 2014 Biochemical Society.


Grant
Agency: European Commission | Branch: H2020 | Program: MSCA-RISE | Phase: MSCA-RISE-2014 | Award Amount: 144.00K | Year: 2015

We are proposing a four-year programme of knowledge transfer and networking between Aston University (ASTON, UK), Universitatsklinikum Erlangen (UKER, Germany) and Redoxis AB (Redoxis, Sweden). Our proposal targets an emerging area of biology, i.e. reactive oxygen species (ROS)-mediated regulation of immune responses; it brings together the application of small molecule candidate drugs to generate ROS, with use of innovative approaches to biomarker identification in models of chronic inflammatory disease. This research has significant potential for application in human health and is of particular relevance to the ageing population. Research training, innovation and knowledge exchange for early career researchers, achieved by combining our cutting edge expertise, is important to extend the EUs reach in this emergent area. Interchange in this way will facilitate and promote our early career researchers to develop into tomorrows research leaders of redox biology in chronic inflammation. It will encourage new, cross-European collaboration between academia and industry ensuring that we maintain our leading position world-wide. This tri-partite consortium brings together groups with highly complementary expertise to exchange knowledge and develop staff: ASTON in the biochemical analyses of ROS, the effects of immune cell thiol oxidation in vitro and ex vivo and biomarker identification; UKER - in animal models of chronic diseases such as rheumatoid arthritis; and Redoxis - in development of novel drugs that stimulate production of ROS from the NOX2 enzyme as means to modulate chronic inflammation. The project objectives and challenges present a balanced mix between industrial application and basic science, which is focused on knowledge transfer and drug development. Through future collaborative funding, we anticipate far-reaching applications of redox modulators to manage chronic disease and increases in knowledge of both autoimmunity and ageing of the immune system.


Kelkka T.,Medicity | Kelkka T.,Karolinska Institutet | Hultqvist M.,Lund University | Hultqvist M.,Redoxis AB | And 3 more authors.
American Journal of Pathology | Year: 2012

The suppressive role of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) complex-derived reactive oxygen species (ROS) in adaptive immunity-driven arthritis models is well established. In this study, we aimed to investigate the role of NOX2 complex-derived ROS in a model of innate immunity-driven arthritis and to identify the ROS-regulated innate receptors that control arthritis. We used collagen antibody-induced arthritis (CAIA), which is a T and B lymphocyte-independent model of the effector phase of arthritis and is induced by well-defined monoclonal arthritogenic antibodies and enhanced by injection of lipopolysaccharide (LPS). CAIA was induced in both wild-type and Ncf1 mutant mice that lack phagocyte oxidative burst, and stimulated with LPS and other agents to activate innate immune responses. We found that both LPS and lipomannan enhanced CAIA more potently in the presence of functional phagocyte ROS production than in its absence. The ROS-dependent enhancement of CAIA was regulated by TLR2, but not by TLR4 stimulation, and was driven by granulocytes, whereas macrophages did not contribute to the phenotype. In addition, we report that collagen-induced arthritis was not affected by the functionality of the TLR4. We report that TLR2 signaling as an important ROS-regulated proinflammatory pathway leads to severe neutrophil-dependent inflammation in murine CAIA and conclude that the TLR2 pathway is modulated by phagocyte ROS to stimulate the development of arthritis. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.


Olsson L.M.,Lund University | Olsson L.M.,Karolinska Institutet | Nerstedt A.,Biovitrum | Lindqvist A.-K.,Lund University | And 5 more authors.
Antioxidants and Redox Signaling | Year: 2012

Aims: The aim of this study was to investigate genetic variants in the gene neutrophil cytosolic factor 1 (NCF1) for association with rheumatoid arthritis (RA). In rodent models, a single-nucleotide polymorphism (SNP) in Ncf1 has been shown to be a major locus regulating severity of arthritis. Ncf1 encodes one of five subunits of the NADPH oxidase complex. In humans the genomic structure of NCF1 is complex, excluding it from genome-wide association screens and complicating genetic analysis. In addition to copy number variation of NCF1, there are also two nonfunctional pseudogenes, nearly identical in sequence to NCF1. We have characterized copy number variation and SNPs in NCF1, and investigated these variants for association with RA. Results: We find that RA patients are less likely to have an increased copy number of NCF1, 7.6%, compared with 11.6% in controls; p=0.037. We also show that the T-allele of NCF1-339 (rs13447) is expressed in NCF1 and significantly reduces reactive oxygen species production. Innovation: This is the first finding of genetic association of NCF1 with RA. The detailed characterization of genetic variants in NCF1 also helps elucidate the complexity of the NCF1 gene. Conclusion: These data suggest that an increased copy number of NCF1 can be protective against developing RA and add support to previous findings of a role of NCF1 and the phagocyte NADPH oxidase complex in RA pathogenesis. © 2012 Mary Ann Liebert, Inc.


Hultqvist M.,Redoxis AB | Olofsson P.,Redoxis AB | Wallner F.K.,Redoxis AB | Holmdahl R.,Karolinska Institutet
Antioxidants and Redox Signaling | Year: 2015

Significance: New insights into the role of reactive oxygen species (ROS) show that activators of the phagocyte NADPH oxidase 2 (NOX2) complex have the potential to be therapeutic in autoimmune and inflammatory conditions. It is, however, essential to elucidate the consequence of targeting the NOX2 complex, as it might lead to different outcomes depending on disease context and specificity, dose, and timing of ROS production. Recent Advances: Increasing evidence is suggesting that the role of the NOX2 complex is far more complex than previously anticipated. In addition to the well-described antimicrobial response, ROS also have immune and inflammatory regulatory effects. Compounds increasing NOX2-dependent ROS production have been shown to be effective both in preventing and in treating inflammatory manifestations in animal models of autoimmune diseases. Altogether, these results suggest the possibility of activating the NOX2 complex for the treatment of autoimmune inflammatory diseases while restoring and maintaining a balanced ROS regulation. Critical Issues: The complexity of the NOX system and the derived ROS is important and must be considered when designing the programs for the development of NOX2-activating drugs, as well as for validation of selected hits, to successfully identify substances effective in treating inflammatory and autoimmune conditions. In addition, it is important to consider the complex downstream immunological effects and safety for drugs that increase the production of ROS. Future Directions: There is a strong potential for the development of ROS-inducing drugs, targeting the NOX2 complex, which are effective and safe, for the treatment of inflammatory autoimmune disorders. In such drug development, one must carefully investigate the pharmaceutical properties, including both efficacy and safety of the drugs. In addition, the immunological pathways of this new treatment strategy need careful examination. Antioxid. Redox Signal. 23, 446-459. © 2015, Mary Ann Liebert, Inc. 2015.

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