EUROTRAPS

"Natural course, pathophysiology, models for early diagnosis, prevention and innovative treatment of TNF Receptor Associated Periodic Syndrome TRAPS with application for all hereditary recurrent fevers"

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 Obiettivo del progetto (Objective)

'The TNF Receptor Associated Syndrome (TRAPS) is a rare disease of innate immunity, caused by mutations in TNFR1. It is characterised by recurrent bouts of fever and pain and mainly affects patients of European ancestry. The development of renal amyloidosis in up to 20% of cases makes it a potentially fatal disease. Corticosteroids and anti-TNF therapeutics have not been consistently effective in controlling attacks and preventing amyloidosis. EUROTRAPS is a multidisciplinary consortium, which by combining ideas, resources, and data from 7 academic participants and 2 SMEs from 6 countries, aims to gain insights into the natural course and pathophysiology of TRAPS, particularly in children. The creation of a European registry for TRAPS patients will facilitate the delineation of scores and outcome measures for diagnosis and treatment. We will examine additional pathways and genes involved in the phenotype. Kit assays will be developed to facilitate identification of disease mutations and susceptibility factors for amyloidosis and resistance to treatment. TNFR1 signalling, apoptosis and IL1 secretion abnormalities associated with TRAPS will be studied. We will also develop in vitro and humanised animal models to investigate innovative therapies. We expect that future developments in TRAPS will impact on all aspects of hereditary paediatric fevers, and thereby improve the wellbeing of patients and their families. A dedicated bipartite committee will undertake the complex task of managing this ambitious project, create a secure intranet, organise regular meetings, issue progress reports, oversee ethical, legal, financial, and gender issues (over 50% of the participants are female), adjust the workplan at each milestone, and guarantee dissemination, exploitation and protection of scientific information. The requested funding will cover salaries (over 200 person/months newly generated employments), equipment acquisition, consumables, and dissemination of knowledge.'

Introduzione (Teaser)

Deregulation of our immune system often causes auto-immune or auto-inflammatory diseases. Since the mechanisms for the majority of these disorders have not been delineated, European scientists joined forces to study the rare genetic disorder tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS).

Descrizione progetto (Article)

TRAPS is characterised by recurrent fever episodes and muscle pains caused by dysfunctional immunity. Although the detailed mechanism underlying TRAPS is still under investigation, mutations in the TNF receptor (TNFR) are believed to affect various inflammatory processes.

Aiming to shed light into the enigma of TRAPS, the EU-funded Eurotraps project brought together leading scientists in the field. The key objective was to gain insight into the natural course and pathophysiology of the disease in children.

The Eurotraps consortium created a European patient registry that included data on epidemiology and clinical presentation, as well as complications of paediatric and adult patients. The distribution of this rare disease in Europe was found to be ubiquitous.

A diagnostic score for TRAPS patients in childhood was elaborated aiming to improve early diagnosis of TRAPS. Additionally, two prototype kits for the easy genetic diagnosis of TRAPS and other recurrent fevers were developed and several new TRAPS mutations were highlighted. At the same time, this data led to the identification of a potential TNFR regulation pathway which may be deregulated in TRAPS patients.

Investigation of various differences among controls and cells carrying a mutated TNFR1 receptor showed aggregates in the cytoplasm and variant production of certain cytokines by patient monocytes. Consensus treatment recommendations for patients carrying structural mutations or a particular genetic polymorphism were formulated. Another important finding of the project was the discovery that the serum amyloid SAA1.1 homozygous genotype conferred a 5.3-fold increased risk for TRAPS patients to develop amyloidosis.

Wishing to find a promising treatment for the disease, the Eurotraps consortium explored various drugs that interfered with cytokine secretion as well as an innovative approach for monocytes to minimise the ongoing inflammatory process. Collectively, the Eurotraps project provided invaluable knowledge which was directly translated to patient care, hoping to improve diagnosis and treatment of TRAPS patients.