NEW-AGE by EU Research

A new age in drug development Improving treatment of neurodegenerative diseases is among the biggest challenges facing modern medicine, yet it is difficult to assess the effectiveness of therapeutic interventions. We spoke to Professor Roland Wolf and Dr Colin Henderson about their work in developing a next-generation platform to help scientists monitor the progression of neurodegenerative disease and identify effective therapies. The development of therapies to combat neurodegenerative diseases is widely recognised as a research priority, with conditions like Alzheimer’s and Parkinson’s set to place an ever-heavier burden on healthcare systems in future. Current treatments are limited in their impact however, while it is difficult to assess the effectiveness of therapeutic interventions, issues central to the work of the New Age project. “One goal of our project is to develop biomarkers that can reflect the progression of a disease at a much earlier timepoint, and give an earlier and more definitive read-out on the efficacy of any therapeutic intervention,” says Professor Roland Wolf, the project’s Principal Investigator. A core aim in the project is to evaluate how informative different stress pathways are as early biomarkers of degenerative disease. “The life and death of cells is dependent on a variety of different pathways. When cells are subject to toxic injury, leading to death, one of these pathways is invariably activated,” explains Professor Wolf. “One major mechanism of the deleterious effects which lead to cell death is through the induction of oxidative stress. That causes damage to the components of cells, leading eventually to cell death.” This is not the initial cause of neurodegenerative disease, yet oxidative stress or DNA damage are thought to play important roles in its progression. Cells are continuously subjected to a certain level of oxidative stress, but normally deleterious effects are prevented through anti-oxidant pathways; in cases of neurodegenerative disease, it is thought that these pathways are overwhelmed by pro-oxidant effects, including free radicals, causing cell death. “The anti-oxidant pathways cannot cope with the level of damage, the level of free radicals that have been generated as a consequence of the toxic effects,” explains Dr Henderson. A reliable method of monitoring levels of oxidative stress could help researchers assess the effectiveness of neurodegenerative disease therapies. “Oxidative stress or DNA damage are integral to the progression of these diseases rather than the initiation, but they go hand-in-hand,” continues 38

Thanks to Rumen Kostov & Francisco Inesta for the preparation of this image.

Professor Wolf. “The main disease models that we are studying are Hutchinson-Gilford Progeria syndrome, Alzheimer’s disease, and Parkinson’s. There’s a significant body of evidence suggesting that oxidative stress and/or DNA damage is an important driver of these diseases.”

disease they become activated,” explains Professor Wolf. The models were developed on the basis that certain genes are known to be regulated by either oxidative stress or DNA damage. “A protein called heme oxygenase 1 is constitutively only expressed at low levels in cells – but is highly inducible by oxidative

One goal of our project is to develop biomarkers that can reflect the progression of a disease at a much earlier timepoint, and give an earlier and more definitive read-out on the efficacy of any therapeutic intervention. Disease models These models are built on earlier research in which genes associated with these three specific diseases were identified. It was previously shown that aberrations, alterations, or mutations in certain pathways result in these diseases; Professor Wolf, Dr Henderson and their colleagues are working with mouse models that reflect these known susceptibilities. “We’ve crossed those disease models with the reporter models of DNA damage, to evaluate whether those pathways are involved in the pathogenesis of the disease and at what time point in the etiology of the

stress,” says Professor Wolf. “Another gene of interest is p21, a marker which responds to DNA damage in cells – another mechanism of cell death. This gene is again only expressed at low levels in many tissues, but it’s highly inducible by DNA damage.” Researchers have introduced a reporter enzyme into either heme oxygenase 1 or p21, from which more can be learned about levels of oxidative stress. When the gene is activated, for example using a compound like paracetamol which is known to cause oxidative stress, a reporter enzyme is produced that allows scientists to monitor

EU Research

NEW-AGE A next-generation platform for catalysing pre-clinical development of drugs against Alzheimer’s and other degenerative diseases of old-age Project Objectives

The goal of our project is to develop biomarkers that can reflect the progression of a disease at a much earlier timepoint, and give an earlier and more definitive read-out on the efficacy of any therapeutic intervention, which can subsequently be tested in clinical trials.............................

Project Funding

The work described in this project has been funded by the European Research Council: Advanced Investigator Award ERC-294533 (REDOX) Proof of Concept ERC-2016-737534 (New Age)

Project Partners

• Dr. Francisco Inesta-Vaquera, University of Dundee, United Kingdom • Prof. Carlos Lopez-Otin and Dr. Clea Barcena. University of Oviedo, Spain • Prof. Bettina Platt. University of Aberdeen, United Kingdom • Prof. Dario Alessi and Dr. Miratul Muqit, Medical Research Council, Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, United Kingdom.

activity levels. “The enzyme activity is reflected in either a fluorescence signal, or by an enzyme-induced colour change to generate blue cells in a tissue section,” outlines Professor Wolf. This provides a visual indicator, so that the level of oxidative stress can be monitored and compared with that in a healthy mouse. “We can look at the signal in a particular target tissue in a control mouse, and compare it to the level of the signal in a mouse carrying the degenerative disease,” explains Professor Wolf. “In control animals you get a low signal, but as the disease progresses, the signal becomes much more intense and affects many more cells in a tissue-specific manner. This demonstrates that the oxidative stress reporter has been activated, so you can conclude that there has been a level of oxidative stress in that cell.”

Disease progression This could enable clinicians to effectively monitor the progression of a disease even before the symptoms become apparent, and potentially assess the effectiveness of therapies in inhibiting oxidative stress or DNA damage. It is not clear whether this would definitively prevent the progression of disease; Dr Henderson says the model will allow researchers to evaluate this by monitoring status over several time-points. “We have selected a number of time-points, ranging from the mid-to-late stage. The late time-points have been chosen to demonstrate that the models do give you a read-out of the disease. The early time-points were to show

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that we have an early biomarker, which reflects the progression of the disease and allows intervention studies to be carried out,” he says. This latter point holds important implications for drug companies in the development and testing of new therapies, something which Professor Wolf is keen to explore further in future. “We have gained some very promising results in the project, and the commercial exploitation of the model is certainly something we would aspire to,” he continues. A number of interventions have already been proposed in the prevention of different degenerative diseases, and the project’s models could be used to assess their efficacy and bring them closer to practical application. While the data that has been gathered in the project is restricted to HutchinsonGilford progeria syndrome, Alzheimer’s and Parkinson’s disease, Professor Wolf says the model systems hold broader relevance beyond degenerative disease. “For example in toxicology, in understanding the safety of man-made or environmental chemicals on the pathogenesis of a disease,” he outlines. The project’s work is more exploratory at this stage however, with Professor Wolf and his colleagues laying the foundations for future research. “Our primary goal in this work is to take the model systems to a position where we can get them into the public domain and get peer-reviewed publications out, which will give us a platform for further development,” he says. “We have had signs of interest from some commercial entities in using the models, which we are currently pursuing.”

Contact Details

Project Coordinator, Professor Roland Wolf University of Dundee United Kingdom Nethergate DD1 4HN DUNDEE United Kingdom T: +44 1382 383134 E: c.r.wolf@dundee.ac.uk W: https://cordis.europa.eu/project/ rcn/207916_en.html Prof Roland Wolf and Dr Colin Henderson

Professor Wolf and Dr Colin Henderson’s research has focussed on the pathways which have evolved to protect cells for the deleterious effects of chemicals and other environmental agents. These pathways are of central importance in the pathogenesis of human disease, in disease prevention and in the development and use of drugs. His research has involved the characterisation of the enzymes systems involved, genetic variability in their expression and the pathways which become activated in response to chemical and toxic insult.