FIGHT-MG

"Myasthenias, a group of immune mediated neurological diseases: from etiology to therapy."

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 Obiettivo del progetto (Objective)

'Myasthenia Gravis (MG) is a heterogeneous rare autoimmune neurological disease affecting the neuromuscular junction (NMJ). The molecular events causing and maintaining MG are still unknown and current treatments do not lead to remission and entail considerable side-effects stressing the need for improved therapies. We will address the: 1. Natural course of disease: determine factors associated with disease onset and/or affecting the course of disease and patients' quality of life in subgroups of MG patients including children, twins, females and elderly patients. 2. Etiology of MG: identify new genetic, epigenetic and environmental risk factors and investigate immunological key molecules associated with MG onset. 3. Pathogenic mechanisms at the NMJ: a) study molecular changes in the NMJ by proteomic, genetic, epigenetic and microRNA analyses in MG patients and experimental models; b) analyze morphological changes at the NMJ in mouse models expressing YFP nerves and mice transgenic for mini-agrin; c) evaluate the capacity of muscle cell satellites from MG patients to regenerate muscle and form new endplates in immunodeficient mice. 4. New diagnostic and monitoring assays: a) identify pathogenic and protective factors in MG sera; b) improve the sensitivity of current assays; c) Identify new biomarkers associated with different MG subgroups by proteomic and microRNA analyses; d) Identify patients' response to treatment and liability to side effects by pharmacogenomic analyses. 5. Novel therapies: a) study new cell-based therapies aimed at regulating the autoimmune response by regulatory T cells or mesenchymal stem cells in humanized mice; b) immunoadsorb pathogenic antibodies; c) test non-cell based immmunomodulatory therapies; d) target epigenetic regulators. This multidisciplinary project linking basic researchers with clinical neurologists, SMEs and several European patient associations should favor a translational approach for improved MG management'

Introduzione (Teaser)

Myasthenia gravis (MG) is a multifactorial disease of genetic and environmental aetiology. Delineating the genetic risk factors and disease triggers is anticipated to aid in the design of novel, targeted therapies.

Descrizione progetto (Article)

MG is a rare autoimmune disorder that affects the neuromuscular junctions, the sites where the nerves attach to the muscle to transmit information. Patients present with abnormal fatigue in various skeletal muscles, which significantly affects their quality of life. Existing therapies are not very effective and often cause uncomfortable side-effects.

Seeking to address this, the EU-funded 'Myasthenias, a group of immune mediated neurological diseases: From etiology to therapy' (http://www.fight-mg.eu/ (FIGHT-MG)) project performed an interdisciplinary investigation into the epidemiology, aetiology and pathological features of MG.

A narrow collaboration between European clinicians, scientists and associations of patients allowed to establish a patient database with information on 4 300 MG patients, the largest collection in Europe, as well as to evaluate the quality of life of the patients.

The main scientific achievements of the project are, first, the identification of several molecules involved in the pathology. To shed light on the genetic and environmental aetiology of the disease, researchers studied monozygotic twins. They found that the epigenetic profile was similar in the twins, even when they were discordant for the disease, but they also detected changes in gene expression that could explain disease onset in the MG versus healthy twin. The work of the consortium focused on molecules implicated in the immune response (IFN type I and TLR), on Th17 cells, on the immune regulator AIRE and on the oncogene VAV1. In a rat model of the disease, they could also detect an immunological imbalance between regulatory T cells and Th17 cells. Secondly, the characterization of the molecular events occurring in the muscle of the MG patients and MG animals. Using mouse models, researchers investigated the molecular pathogenesis of MG by observing morphological alterations in affected muscle. In humans, they identified deregulation in certain miRNA molecules and developed novel assays for the detection of autoantibodies and other serum biomarkers. New biomarkers of therapeutic significance were discovered that could be used to reliably predict the response to certain drugs. Thirdly, the development of innovative therapies. Researchers also developed novel molecular and cell-mediated therapies based on the use of regulatory T cells or mesenchymal stem cells. Treatment with epigenetic regulators or the administration of plasminogen mutant protein showed considerable efficacy in MG animal models.

Taken together, the FIGHT-MG study sheds light on the mechanism of the disease and proposes new promising therapeutics. The more sensitive assays developed during the project should enable prompt diagnosis and help alleviate disease symptoms through early therapy.