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1) Dr. Giovanna Zambruno Laboratory of Molecular and Cell Biology,

Project Participants. 1) Dr. Giovanna Zambruno Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell’Immacolata; Rome, Italy 2) PD. Dr. Luca Borradori Clinique de Dermatologie Hopital Cantonal Universitaire de Genève, Switzerland 3) Prof. Leena Bruckner-Tuderman

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1) Dr. Giovanna Zambruno Laboratory of Molecular and Cell Biology,

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  1. Project Participants 1)Dr. Giovanna Zambruno Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell’Immacolata; Rome, Italy 2) PD. Dr. Luca Borradori Clinique de Dermatologie Hopital Cantonal Universitaire de Genève, Switzerland 3) Prof. Leena Bruckner-Tuderman Universitaetsklinikum Freiburg, Germany 4) Prof. Michael Hertl Department of Dermatology, University of Erlangen, Germany 5) Dr. Guerrino Meneguzzi, INSERM U385, Nice, France 6) Prof. Jörgen Wieslander, Wieslab AB, Lund, Sweden (SME) Project duration: 3 years Total project costs: 1.352.948 Euro EC contribution: 865.814 Euro + 189.698 from CH

  2. The pemphigoids (PEs) A group of rare, chronic autoimmune disorders of the skin and mucous membranes characterised by sub-epidermal blisters and mediated by autoantibodies targeting different epithelial adhesion molecules. The PEs comprise: bullous pemphigoid (BP) (most common PE, estimated incidence 6-7cases/106/yr) gestational pemphigoid (GP) and mucous membrane pemphigoid (MMP)

  3. Keratin tonofilaments (K5/K14) BP230 Basal keratinocyte (BK) PLECTIN Hemidesmosome (HE) a6 4 6 BP180 Lamina lucida (LL) Laminin 5 Lamina densa (LD) Collagen VII Anchoring fibrils (AF) The hemidesmosomal adhesion complex in stratified epithelia Epidermis BK Cutaneous basement membrane zone HE LL LD AF

  4. Keratin tonofilaments (K5/K14) BP, PG, MMP BP230 PLECTIN BP, GP, MMP a6 4 6 BP180 MMP Laminin 5 MMP Collagen VII Antigens of the hemidesmosomal adhesion complex targeted in the PEs Basal keratinocyte Hemidesmosome Lamina lucida Lamina densa Anchoring fibrils DIF: IgG deposits in BP patient’s skin

  5. PEs autoantigens are also the defective proteins in a group of genetic skin diseases, inherited epidermolysis bullosa Keratin tonofilaments (K5/K14) BP230 PLECTIN Junctional Epidermolysis Bullosa a6 4 6 BP180 Laminin 5 Collagen VII Defective epithelial-mesenchymal adhesion  severe and lethal phenotypes

  6. Project Objectives To obtain novel knowledge on epithelial adhesion mechanisms (1) To define the molecular interactions involved in the assembly of hemidesmosomes and in maintenance of epithelial-mesenchymal adhesion; (2) to define the physiological function of the processing of epithelial adhesion proteins, namely BP180 and L5 To achieve a better understanding of PEs immunopathogenesis; to define diagnostic and prognostic markers and to develop diagnostic tools and novel therapeutic strategies (1) To characterize the humoral immune response to epithelial adhesion proteins (BP180, BP230, and L5) in the PEs and to identify laboratory markers predicting disease activity and outcome; (2) to establish the role of the processing products of BP180 and L5 as antigens in the PE; (3) to characterize autoreactive T cell responses to BP180 in the PEs; (4) to identify elderly individuals at risk for development of bullous pemphigoid

  7. The pemphigoids, autoimmune blistering diseases of the skin and mucosae: immunopathogenic mechanisms, diagnostic and prognostic markers • CO-ORDINATOR • Scientific co-ordination • Administrative co-ordination WORKPACKAGES • EPITHELIAL ADHESION MACHINERY: • PHYSIOLOGY • WP1: Molecular interactions of • epithelial adhesion proteins • targeted in the PEs • Partner Responsible: 2, 5 • Partners Involved: 1, 2, 5 • WP2: Processing of epithelial adhesion • proteins (BP180 & laminin 5) • Partner Responsible 3 • Partners Involved: 3, 5 • IMMUNOPATHOGENESIS, DIAGNOSIS, • PROGNOSIS, THERAPY • WP3: Humoral immune responses • Partner Responsible: 1 • Partners Involved: 1- 6 • WP4: T cell immune responses • Partner Responsible 4 • Partners Involved: 2, 4 • EARLY DIAGNOSIS • WP5: Elderly individuals at risk for • development of bullous pemphigoid • Partner Responsible: 2 • Partners Involved: 1- 4, 6 Diagnostic tools Antibodies DELIVERABLES • Recombinant molecules • Diagnostic tools (ELISA & ELISPOT) • Markers of disease severity, course & prognosis • Immunotherapy tools and strategy • Markers for early diagnosis • Recombinant molecules • Antibodies • Animal model

  8. Exploitation & dissemination activities • PUBLICATIONS • 19 articles published in peer-reviewed journals (2 J Biol Chem, 1 EMBO J, 1 Mol Biol Cell, 1 Am J Pathol, 1 J Histochem Cytochem, 7 J Invest Dermatol, 1 Matrix Biol, 1 Prot Exp Purif, 3 Br J Dermatol, 1 Exp Dermatol) (7 articles in collaboration between 2 or more partners) • 3 manuscripts in revision or submitted • 5 manuscripts in preparation PROJECT WEBSITE: http://www.idi.it/qlg1-ct-2001-02007/eu/map.htm • FORECASTED/ACHIEVED () TECHNICAL DELIVERABLES • Eukaryotic-expressed recombinant polypeptides • An animal model for laminin g2 chain processing  • Antibodies for BP180 and BP180 neoepitopes • ELISAs for BP180 , BP230 , L5 , and BP180 neoepitopes • ELISPOT/MACS assay for BP180-reactive T cells  • Tools for a specific immunotherapy of BP and immunologically related disorders

  9. PEMPHIGOIDS & IMMUNITY: small size collaborative RTD project • In a specific (but limited) group of rare diseases: • Significant advance in understanding of disease mechanisms • Identification of laboratory markers of disease activity, relevant to patients’ treatment and follow-up • Technological developments (antibodies, diagnostic tools) • Disease rarity limits the interest for patenting project deliverables (e.g. diagnostic ELISA tests) • Disease chronic course requires a more extended project duration to develop clinical studies with an adequate follow-up period • Considering disease rarity, the amount of project funding to SME appears insufficient to encourage the development of long-term research projects leading to marketable diagnostic or therapeutic products

  10. GENESKIN RARE GENETIC SKIN DISEASES: ADVANCING DIAGNOSIS, MANAGEMENT AND AWARENESS THROUGH A EUROPEAN NETWORK COORDINATION ACTION - EU FP6

  11. Genetic skin diseases: state of art • Huge number ( 300) of rare but disabling and often life-threatening diseases and syndromes affecting predominantly the skin. Very limited data about disease epidemiology; significantly different levels of knowledge of causative genes, function of their protein products and diseases pathogenesis in the various diseases • Diagnostic problems: often complex diagnostic procedures requiring both in-depth clinical knowledge and specific laboratory techniques (biochemical assays, immunohistochemistry/immunofluorescence, electron microscopy, molecular biology assays). Molecular diagnosis and DNA-based prenatal diagnosis nowadays possible (but extremely expensive) for a significant number diseases • Management problems: multidisciplinary healthcare teams often required for proper management, no curative therapy available, development of new therapeutic approaches and clinical trials hampered by limited Company interest and small number of patients • A limited number of centres in Europe are organised to deal with these diseases and, even then, their expertise is limited to a restricted number of specific diseases

  12. GENESKIN • Project duration: 3 years • Project starting date: 01/07/2005 • Participating centres: 32 (27 legal entities) clinical and research centres from 12 European countries • EC contribution: 1.238.200 Euro

  13. GENESKIN: project objectives • To create a European network for five major groups of genetic skin diseases that, through a dedicated website, will contribute to disseminate disease knowledge and awareness, improve diagnosis and management, facilitate access to novel treatment options • To integrate, test and validate diagnostictools and to facilitate research for genetic skin diseases • To organise training on clinical, diagnostic and management aspects of specific disease groups • To promote pan-European communication pathways among patients’ organisations, ethic committees, physicians and scientists

  14. GENESKIN Epithelial adhesion disorders Ectodermal dysplasias DNA repair disorders Connective tissues disorders Keratinization disorders • Clinical and diagnostic needs and tools; • Generation, submission and updating of disease-related clinical and diagnostic information; • Standardization and validation of diagnostic tools; • Training in clinical and diagnostic activities; • Accompanying measures: patient-related and ethical activities • WEB-BASED INFORMATIC PLATFORM • Reference center list • Protocols/questionnaires for diagnosis • Available tool box (reagents, gene cards) • Mutation data base • Disease-related web-sites and clinical trial list • News and views

  15. WP1 Epithelial adhesion disorders • Blistering disorders of skin and mucosae due to defective epithelial-mesenchymal adhesion [epidermolysis bullosa (EB) group and Theresa Kindler syndrome (KS)] • State of art: all causative genes identified, function of most disease-gene products known, molecular classification established, molecular and prenatal diagnosis available inreference centres EB simplex Dystrophic EB Junctional EB KS

  16. WP3 Ectodermaldysplasias (ED) • >100 different syndromic diseases, mostly extremely rare, presenting abnormalities of two or more ectodermal structures [hidrotic ED; hypohidrotic ED (EDA); EDA with immunodeficiency; incontinentia pigmenti (IP); palmo-plantar keratodermas; AEC syndrome; EEC syndrome; Rapp-Hodgkin syndrome; ectodermal dysplasia, Margarita island type; tooth and nail syndrome; Ellis-van Creveld syndrome; limb-mammary syndrome; etc] • State of art: molecular basis of a number of ED still unknown, function of only a few gene products characterised, diagnostic challenge, need for a revised classification EDA IP

  17. Objectives WP1-5 For each disease group: • To provide and update a reference centre list with specification of services offered (clinical facilities, diagnostic techniques) • To generate model questionnaires/protocols for disease diagnosis • To provide diagnostic reagent lists (antibodies, enzymatic tests, primer sets and protocols for mutation screening) • To generate and update gene cards and a mutation database(for each disease, mode of inheritance and list of mutations with associated phenotypes) • To generate and update a database with clinical trials • To identify disease-related websites in different countries • To provide information on recent developments in the field

  18. WP1 Epithelial adhesion disorders WP2 Keratinization disorders WP3 Ectodermal dysplasias WP4 Connective tissue disorders WP5 DNA repair disorders GENESKIN website • Reference center list • Protocols/questionnaires for diagnosis • Available tool box (reagents,gene cards) • Mutation data base • Disease-related web-sites and clinical trial list • News and views Section addressed to the public Section addressed to physicians/scientists/healthcare providers

  19. WP7 Standardization and validation of diagnostic tools Aims: • To organize a "virtual" sample databank by sharing the information relative to the biological material for selected diseases • To recruit informative families and biological samples for gene mapping studies in specific diseases • To test and validate novel antibodies and enzymatic tests to be used in the diagnostic protocol of specific diseases • To standardise/test techniques for mutation analysis of selected genes

  20. WP8 Training Aim: to organise and deliver both individual and common training for physicians, healthcare personnel and laboratory personnel in order to disseminate knowledge about genetic skin diseases Individual training: One-week courses delivered in selected reference centers for specific disease groups. Topics: clinical presentation/diagnosis and treatment options, laboratory diagnosis tools and procedures, genetic counselling, database handling, ethical aspects Common training: Workshops held at the occasion of the second and third project general meetings. Topics: diagnosis, therapy, newest developments in each disease group; ethical, socio-psychological and information science aspects

  21. Linkage to the community - the accompanying network of non-medical public GENESKIN-representatives WP9 Aims: Through a close co-operation of physicians and scientists with public non-medical groups, i.e. patients organisations and ethic committees: • To develop and maintain a balanced dialog among these different parts, • To insure that patient specific needs are integral part of medical and/or scientific decisions, in agreement with ethical values • To raise public awareness about rare diseases • Specific objectives: • To establish of a European GENESKIN Patients Association • To prepare a GENESKIN information kit for the non-physician/scientist • To organise regular interaction and combined activities of public groups with physicians and scientists

  22. WP1 Epithelial adhesion disorders WP2 Keratinization disorders WP3 Ectodermal dysplasias WP4 Connective tissue disorders WP5 DNA repair disorders WP7 Diagnostic tools WP8 Training WP9 Linkage to the community GENESKIN website • Reference center list • Protocols/questionnaires for diagnosis • Available tool box (reagents, gene cards) • Mutation data base • Disease-related web-sites and clinical trial list • News and views • Virtual sample databank • Project training activities • Project patients-related and ethical activities Section addressed to the public Section restricted to project participants Section addressed to physicians/scientist/healthcare providers

  23. GENESKIN: large size coordination action • For five major groups (but not all) of genetic skin diseases: • Establishment of a European task force aggregating clinical and research centres dealing with these diseases (possible future adviser role in identifying specific research needs in genetic skin diseases) • Facilitated information for both health professionals and patients/general public • Improved diagnosis, facilitated patients’ access to diagnosis and treatment, and, overall, improved patient care • More appropriate response to specific accompaniment needs of patients and their families • Increased public awareness about rare diseases • Limited funding does not allow to develop comprehensive measures for all diseases • Further support needed for the establishment of database and biological material collections • Further support needed for specific research actions varying according to present level of knowledge of the different diseases

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