EuroTRAPS, a consortium for new therapeutic models in TNF receptor Associated Periodic Syndrome and hereditary recurrent fevers

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1 EuroTRAPS, a consortium for new therapeutic models in TNF receptor Associated Periodic Syndrome and hereditary recurrent fevers Isabelle TOUITOU Medical Unit for Auto Inflammatory diseases Hôpital Arnaud de Villeneuve, Montpellier Team: Genetics of AutoInflammatory diseases Institute of Human Genetics, CNRS, UPR1142 Montpellier

2 EuroTRAPS, a consortium for new therapeutic models in TNF receptor Associated Periodic Syndrome and hereditary recurrent fevers What is TRAPS? Current hypotheses on TRAPS mutations From pathophysiology to new treatments EuroTRAPS : who and why?

3 What is TRAPS? Rare dominantly inherited multisystemic disorder (OMIM ) First description: Northern European ancestry (Hibernian fever) but has been described now in almost all ethnic groups Key clinical features in TRAPS patients (from Stojanov 2005) Symptom Fever Abdomen Muscles Skin Joints Eyes Amyloidosis Miscellaneous Characteristics Mean attack duration: 2 weeks Acute pain leading to surgical event in 33% cases Centrifugal myalgia, tenderness, cervical stiffness Erythema (rarely urticaria), same area as myalgia Arthralgia, arthritis Periorbital oedema, conjunctivitis Serious long term complication (renal failure) Pleuritis, pericarditis, pharyngitis, CNS illness Frequency 95% 77% 64% 55% 51% 49% 20% Courtesy of Pr I Koné Paut

4 The TRAPS mutations McDermott MF, Aksentijevich et al. Ger mline mutations in the extracellular domains of the 55kDa TNFR1 define a family of dominantly inherited autoinflammatory syndr omes. Cell G/T 580 A/G 383 A/C 36 G>A 5 flanking D12E Y20H Y20D H22Y H22Q S27S C29F C29Y C30R C30S C30Y C30F C33G C33Y (GT)n(GA)n I1 G36E T37I Y38C L39F D42del C43R C43Y C43S P46L G47G T50M T50K C52R C52F C52Y E54E C55R G>A _ 17del C>T G>A I2 C55S C55Y F60L F60V F60S T61I N65I L67P H69fs C70R C70S C70G C70Y C73R C73W S74C A>G I3 S86P C88R C88Y R92W R92P R92Q T94T V95M C96Y C98Y R104Q H105P E109A F112I I G>A 472+6C>T C>T G>A C>T G>A A>T I5 TNFRSF1A (12p13.2) INFEVERS: September 04, 2008 N Sequence variants: 86 K157K L167_G175del I170N V173D G>A 740 9T>C S197S I6 I7 I8 I flanking

5 Effect of TNFRSF1A mutations: Current hypotheses from Simon and Van der Meer, 2006 (a) TNFR1 molecules are transported from endoplasmic reticulum to the Golgi, where they are pooled before going on to the surface. (b) When TNF binds to the cell surface TNFR1 trimer, intracellular signaling results in NF kb activation and/or apoptosis. (c) Upon activation, cell surface receptors are cleaved off by metalloproteinase (shedding). These soluble receptors act as natural TNF antagonists.

6 Effect of TNFRSF1A mutations: Current hypotheses from Simon and Van der Meer, 2006 (d) Defective shedding Reduced cleavage following stimulation >>> increased TNFR1 expression on the membrane >>> uncontrolled inflammation (e) Defective TNF induced apoptosis Mechanism?? >>> Sustained activation of inflammatory cells during fever episodes. (f) Defective intracellular TNFR1 trafficking and TNF binding Clear accumulation of the protein in the endoplasmic reticulum associated with impaired signaling of both pro apoptotic and pro inflammatory pathways after cell stimulation. (g) TNF independent NF kb activation Increased activation of the p65 subunit of NF kb in the absence of TNF.

7 From pathophysiology to new treatments Classic (Empirical) treatments Glucocorticoids: Act as repressors of transcription factors e.g. NF κb Usually effective in TRAPS But side effects : Steroid dependency, Growth delay in children Colchicine and immunosuppressive drugs: Effective in other inflammatory diseases Ineffective in TRAPS Solution for r efr actor y patients? (r isk of r enal amyloidosis!)

8 From pathophysiology to new treatments Anti TNF (Etanercept; receptor superfamily 1A fusion protein) First trial : Drewe E et al. Treatment of the nephr otic syndr ome with etanercept in patients with TRAPS. N Engl J Med Oct 5;343(14): Etanercept may reverse or slow the progression of systemic AA amyloidosis Prospective studies : Hull KM, Drewe E, Aksentijevich I et al: The TRAPS: emerging concepts of an autoinflammatory disorder. Medicine (Baltimore) 2002; 81: Initial positive response in the frequency and intensity of inflammatory episodes This response tends to wane over time and some patients developed amyloidosis Etanercept does not abolish inflammatory attacks but improves disease activity allowing corticosteroid reduction

9 From pathophysiology to new treatments Anti IL 1 (Anakinra; recombinant IL 1receptor antagonist) First trial : Simon A et al. Beneficial response to interleukin 1 receptor antagonist in TRAPS Am J Med Aug 1;117(3): Prospective studies : Gattor no M et al. Persistent efficacy of anakinra in patients with TRAPS Arthritis Rheum May;58(5): Continuous treatment with anakinra effectively controlled both the clinical and laboratory manifestations in patients with TRAPS and prevented disease relapses Only 6 published patients

10 Natural course, pathophysiology, models for early diagnosis, prevention and innovative treatment of TRAPS with application for all hereditary recurrent fevers Montpellier University Hospital Centre INSERM (National Institute for Health and Medical Research) Leeds Institute of Molecular Medicine, St James University Hospital University College of London "G. Gaslini" Scientific Institute for Children University Hospital IRCCS Policlinico San Matteo University Children s Hospital Charité Pronto Diagnostics Ltd. (SME) ViennaLab Diagnostics GmbH (SME) FR (Montpellier) FR (Montpellier) UK (Leeds) UK (London) IT (Genova) IT (Pavia) DE (Berlin) IL (Rehovot) AT (Vienna) and main partners a. Isabelle TOUITOU b. Valérie THORIN Flor ence APPARAILLY Michael McDERMOTT Helen LACHMANN a. Marco GATTORNO b. Isabella CECCHERINI c. Alberto MARTINI Laura OBICI Kirsten MINDEN Nir NAVOT Christian OBERKANINS Coor dination

11 OVERALL STRATEGY OF THE EUROTRAPS PROJECT PATIENTS with TRAPS phenotype Informed consent LABORATORIES Immuno therapy scientists Molecular geneticists WP2.Natural course Paediatric features Registry Quality of life Outcome CLINICIANS Paediatricians Rheumatologists Therapeutics experts Dissemination Intranet WP1.Management Budget Valorisation SMEs WP3.Development of diagnosis Diagnostic score for paediatric patients Quality control Novel diagnostic kit Characterization of TRAPS like genes WP5.Prevention Identification of genetic and clinical susceptibility factors associated with complications WP4.Therapeutic approaches Survey of current therapies Identification of outcome measures Identification of genetic signature for response to treatment WP6.Pathophysiology TNFR1 signalling and trafficking, apoptosis, IL1β expression WP7.Development of innovative therapeutic models Candidate (anti IL1) and innovative (RNAi) alternative therapies using in vitro and humanized animal models

12 WP6. Pathophysiology Functional consequences of TRAPS mutations in physiological in vitro models Michael McDERMOTT New doxycycline dependent TNFR1 expression system >> Study of molecular interactions between these receptors at both physiologic and pathophysiologic levels of expression Youssaf et al, A&R: 2005 TNF Dox Other mutations? IP: Heterotrimer formation by T50K TNFRI with WT TNFRI subunits. EMSA: T50K TNFRI expression activates NF B independently of TNF

13 WP7. Development of innovative therapeutic models RNAi using in vitro and humanized animal models Florence APPARAILLY Cationic liposome sirna 1. Validation of sirna sequences specific for the TNF and IL 1B silencing in TRAPS monocytes Lipoplex: non viral vector 2. Investigation of systemic delivery of sirna in humanised model of activated TRAPS leukocytes in SCID mice Expected: Initial assessment of factors associated with therapeutic efficacy Definition of optimal conditions for RNAi based gene therapy for further pre clinical studies.

14 Potential advances that EUROTRAPS will bring about: Improvement of TRAPS patient diagnosis, care and quality of life Improvement in our knowledge of the genetics and pathophysiology of TRAPS Improvement of present and future treatment Evaluation of conventional anti cytokine therapies Definition of new markers of disease severity and response to treatment Development of innovative therapies: new IL 1 blockers and sirna approaches