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Neuroprotective strategies for multiple sclerosis - Project presentation |
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Contract number: LSHM-CT-2005-018637
Project acronym: NeuroproMiSe
Project name: Neuroprotective strategies for multiple sclerosis
Priority/Strategic objective: Life Sciences, genomics and biotechnology for health/Combating major diseases: Neuroimmune disorders: From basic to clinical research.
Project logo:
List of participants:
Istituto Superiore di Sanità,Italy
University of Göttingen, Germany
Lund University, Sweden
Medical Research Council, UK
Medical University of Vienna, Austria
INSERM, France
Max-Planck Institute of Experimental Medicine, Germany
Karolinska Institute, Sweden
National Public Health Institute, Finland
Southampton University, UK
King's College London, UK
University of Stuttgart, Germany
Groningen University, The Netherlands
The Hellenic Pasteur Institute, Greece
HyCult biotechnology b.v., The Netherlands
Arexis AB, Sweden
Eisai,UK
University of Bonn, Germany
Direvo Biotech AG, Germany
Project main goals:
Axonal damage and neuronal loss are responsible for clinical deterioration in multiple sclerosis (MS), the most common inflammatory disease of the central nervous system (CNS), but effective therapies to prevent neurodegeneration are still lacking. The overall aim of the NeuroproMiSe project is to elucidate the molecular mechanisms underlying inflammation-driven injury of the CNS and to define and validate novel targets for the development of therapies for debilitating CNS inflammatory diseases. NeuroproMiSe will achieve this goal through a disease-oriented approach by identifying the essential genes and pathways leading to MS and by direct protection of axons/neurons through targeting of critical signalling pathways.
Key issues:
Within the NeuroproMiSe project, several European laboratories with profound expertise in genetics, basic neuroscience, neuropathology, neuroimmunology, protein chemistry and experimental models of neuroinflammation and neurodegeneration are collaborating with industrial partners with a strong interest in developing therapeutics for inflammatory and neurological diseases. This consortium will integrate their research potential to identify genes and pathways associated with disease susceptibility and course in experimental models of MS and neurodegeneration, and will use this information to define synonymous genes in homogeneous and well characterized cohorts of MS patients and population-based controls. By transcriptome and proteome analyses, new molecules and pathways involved in inflammatory and non-inflammatory neurodegeneration will be identified in selected disease models. The consortium will validate the role of candidate genes in a range of disease and in vitro models and, based on this knowledge, will develop new therapeutic compounds. New, genetically engineered mice will be generated that represent invaluable tools for both basic research and disease modelling. By detailed analysis of human material and relevant disease models and by exploring the involvement of the innate and adaptive arms of the immune system in CNS tissue destruction, the NeuroproMiSe project also aims to provide new insights into inflammatory mechanisms responsible for neuronal and glial cell damage and to define biomarkers for evaluation of pathogenic processes and responsiveness to therapeutic treatments. Moreover, the project will use anti-inflammatory and neuroprotective compounds, recently generated in the applicants' laboratories, to develop novel and combined therapeutic strategies to prevent inflammation-driven neurodegeneration. Although a large part of the work will be performed in MS patients and experimental models of MS, the knowledge and tools generated will also enhance understanding of pathogenetic mechanisms and allow development of new therapeutic approaches in other acute and chronic neuroinflammatory disorders.
To accelerate the achievement of the NeuroproMiSe objectives, horizontal activities will be developed through the establishment of neuropathology and genomics/proteomics facilities and training programmes. This will ensure the uniform availability and distribution of technological know-how in cutting-edge technologies of lesion analysis/imaging and functional genomics.
Technical approach:
The NeuroproMiSe Project as a whole focuses on translational research and uses basic and functional genomic and proteomic knowledge for translation into therapeutic concepts and further into preclinical application. A unique platform of mouse and rat congenic strains will be used for identification of disease-susceptibility genes and associated molecular pathways in experimental models of MS and neurodegeneration, and for the study of gene-gene and gene-environment interactions. To characterize the allelic diversity of known MS risk genes and of selected genes identified in the experimental genetic platforms, high-throughput single nucleotide polymorphism (SNP) genotyping and haplotype analysis will be carried out in selected cohorts of Finnish and Swedish patients with MS. High throughput gene expression profiling using cDNA microarrays and proteomic analysis of CNS tissue will be performed in relevant experimental models, to specifically search for molecules/pathways involved in neurodegeneration and identify new targets for neuroprotective strategies as well as novel biomarkers to monitor MS progression and response to therapy. Validation of candidate genes and mechanistic pathways will be performed by gene and protein expression analysis and bioinformatics, and by using a wide array of already-existing and to-be-developed genetically modified mice (knock-in, knock-out and knock-down) in relevant disease models and functional assays. Targets identified and validated in the above studies will provide seeds for the development of new therapeutic compounds.
Improved transgenic models will be generated to investigate the role of adaptive (T cells, B cells) and innate (macrophages/microglia) immune cells in mediating CNS tissue damage. Based on the information obtained, new disease-modifying strategies and compounds will be developed and tested in laboratory models of MS. A number of critical pathways of neurodegeneration and neuroprotection will be investigated further and different approaches will be undertaken to achieve neuroprotection, including: i) development and testing of compounds targeting molecules that are involved in the regulation of myeloid cell function; ii) application of genetic engineering and nanotechnology to develop compounds targeting tumor necrosis factor receptor subtypes and intracellular signalling; iii) evaluation of the efficacy of new sodium and calcium channel blockers and of glutamate receptor antagonists in axonal protection; iv) manipulation of intracellular pathways involved in neuronal apoptosis with neurotrophic factors, pharmacological approaches or new protein transfer tools; v) evaluation of the therapeutic efficacy of combined neuroprotective and anti-inflammatory compounds in disease models. The generation of new compounds, which will be tested for their anti-inflammatory and neuroprotective efficacy, and of bifunctional molecules for targeting of neuroprotective activities specifically to neurons and glial cells will permit the application of innovative approaches for the treatment of neuroinflammatory diseases.
Expected achievements/impact:
It is expected that with the knowledge acquired about specific genes and pathways involved in inflammatory neurodegeneration and neuroprotection, and with the compounds developed on the basis of this knowledge, within the five years of the project candidate therapeutic molecules will be made available and proposed for subsequent clinical evaluation. All together, the planned activities of the NeuroproMiSe consortium will represent a significant advance of the state of the art. Knowledge and products generated will speed up effective treatment of neuroimmune diseases, contributing towards the improvement of quality of life and health and promoting biotechnology and pharmaceutical industry. Updates on the NeuroproMISe Project activities will be available in the website www.neuropromise.org
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