Project: Neuroprotective therapy for ischemic stroke
Inhibition of the NADPH oxidase isoform, Nox4, with specific and selective Nox4 inhibitors has the potential to become a safe and efficient therapy for ischemic stroke. Such a therapy will be the first mechanism-based, neuroprotective therapy on the market. It will fulfil a huge medical need for more effective stroke therapies and thus lowers healthcare costs and improves wellbeing of affected patients. This project is based on Glucox Biotech's proprietary set of Nox4 inhibitors, which we will further develop._x000D__x000D_In normal metabolism seven isoforms of NADPH oxidases generate reactive oxygen species (ROS). ROS function as second messengers that regulate various cellular activities, including for example immunological defence, cell proliferation, cell differentiation and insulin signalling. Hyperactivity of some of the Nox isoforms has been suggested as an important driver in a number of diseases, including cardiovascular diseases such as hypertension, heart failure and ischemic stroke. It has also been involved in diabetes and diabetes-associated complications, cancer, Alzheimer’s disease, as well as in Parkinson’s disease. Compared to the other isoforms, Nox4 is unique, since it releases hydrogen peroxide, whereas the other family members generate superoxide. Nox4 also is the only isoform with an inducible, constitutive activity that is independent of interaction with cytosolic binding Ps._x000D__x000D_Glucox Biotech (GB) aim is to bring new Nox inhibitors to the market, primarily as new drugs, but also as valuable research tools for improving knowledge on the role of different Nox isoforms in health and disease. GB has previously identified and characterized several sets of small molecules inhibiting Nox activity including compounds targeting Nox4 with high specificity and isoform selectivity. Some of these compounds represent excellent starting points (leads) for the further development into pharmaceuticals. _x000D_GB is a member of a COST Action, EU-ROS (BM1203). EU-ROS has the goal to improve knowledge related to ROS and to facilitate the process to bring new respective products to the market by enabling a network of institutions and companies working in the field. Through EU-ROS GB and Professor Harald Schmidt, Maastricht University (UM), established collaboration on the role of Nox4 in ischemic stroke and developing Nox4 inhibitors for this indication._x000D__x000D_Here, we aim to further optimize Nox4 inhibitors that GB has identified as drugable compounds and already have been used in vivo._x000D__x000D_New drugs for ischemic stroke are urgently needed as it not only accounts for approximately 80% of all cases of stroke, but also is the second leading cause of death in the world. It thus causes a huge burden for patients and societies, which is expected to further escalate with an aging population. Only one drug is approved for ischemic stroke. More alarmingly, over 30 contra-indications exclude most patients from the treatment with this drug. Thus, new neuroprotective treatments are essential to decrease the burden._x000D__x000D_Recently, the group of Prof. Schmidt provided the proof of concept that NOX4 represents a highly promising novel, mechanism-based therapeutic target for ischemic stroke. The group showed that deletion of NOX4 in mice, but not of NOX1 or NOX2, not only massively reduces infarct sizes upon ischemic strokes, but also results in better neurological outcomes, protection of the blood-brain-barrier, and improved survival. To provide a translational proof of concept, Schmidt et al. used an NOX inhibitor, which is, however, not isoform-specific and which likely has some off-target effects. Nevertheless, post stroke application of this compound in a clinically relevant time frame was as neuroprotective as deletion of NOX4 in WT mice. However, it did not have an additional effect in NOX4 deficient mice, showing that NOX4 indeed is the detrimental source of ROS in ischemic stroke (Schmidt et al., Plos Biol 2010). As deletion of NOX4 in mice does not result in any apparent basic phenotype, its acute inhibition in humans after ischemic strokes is likely a safe therapy. Moreover, treatment of stroke patients with NOX4 inhibitors should not increase the risk of bleedings in case of a haemorrhagic stroke, as it is currently the case for the approved drug. Thus, the treatment could be started without the need for a CT scan. Additionally, two of the Nox4 inhibitors isolated by GB, to be further developed in this project, demonstrated significant reduction in infarct size upon ischemic stroke. One of these inhibitors has an 8-fold selectivity for Nox4 over Nox2. _x000D__x000D_In summary, Nox4 is a highly promising mechanism-based therapeutic target for the treatment of ischemic stroke. Through collaboration with UM, GB therefore aims to further develop their Nox4 inhibitors, including lead optimization, pharmacokinetics, ADMET, formulation development, proof of principle in animal studies and preclinical toxicology._x000D_
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Acronym
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NOX4IS
(Reference Number: 8155)
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Duration
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01/11/2013 - 31/10/2016
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Project Topic
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Ischemic stroke is a major cause of death and disability, and no neuroprotective therapy is available. Thus, our consortium aims to develop the first pharmaceutical for ischemic strokes that reduces neuronal cell death, improves the wellbeing of patients and lowers the economic burden of societies.
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Network
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Eurostars
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Call
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Eurostars Cut-Off 10
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Project partner
