The research group “Translational Genomics” will constitute the genomics resource of the team, and coordinate translational research projects focused on the applicative development of novel genome analysis technologies, with the aim of improving genetic diagnosis in clinical applications, and novel gene identification. Efforts will be made specifically to further increase diagnostic yields and validate the implication of novel genes in neuromuscular diseases through (i) the adaption of Whole-exome and Whole-genome Next Generation Sequencing (NGS), and (ii) the development of functional tests for the characterization of the pathogenic impact of sequence variants, the latter points will be enriched and positioned in a highly propitious research environment through the close collaborations with the group lead by Pr. C. Béroud (Bioinformatics and genetics), the group led by Dr. F. Magdinier (Epigenetics, Chromatin & Disease modeling), and the newly created genomics platform of our Research Unit headed by Dr. V. Delague.
The “Translational Genomics” relays on our expertise acquired in this field during the past 8 years, in particular through our participation to four FP7 European Projects (NMD-CHIP, BIO-NMD, LEB’IN and NEUROMICS), the MYOCAPTURE project, and longstanding collaboration-networks in the Mediterranean area (A*MIDEX RARE-MED project) Moreover, this group is closely linked to the diagnostic activities and the constitution of large national and international cohorts within the Department of Medical Genetics of Marseille (Hôpital d’Enfants de La Timone; Assistance Publique - Hôpitaux de Marseille), in strong relationship with the Reference Center for Neuromuscular Diseases and Lateral Amyotrophic Sclerosis in Marseille (Pr. J. Pouget and Pr. S. Attarian). Noteworthy, for different types of neuromuscular diseases on which our “NMD Department” focuses (i.e. Dysferlinopathies, Calpainopathies, GNEpathies, FSHD, different forms of CMT-neuropathies), the Department of Medical Genetics of Marseille is the national French reference laboratory for genetic diagnosis, receiving the large majority of patient samples throughout France.
Using innovative approaches, we will identify new defective genes/proteins in NMD diseases. This group “Physiopathology of neuromuscular disorders” will focus on the comprehension of the pathomechanisms underlying the diseases caused by these new mutations/disease genes. The objectives here are to pave the way for the development of new therapies, by i) studying the physiopathological mechanisms underlying the studied diseases, due to mutations in new defective genes in NMD, or new mutations in genes already involved in other hereditary diseases (NMD or not); and ii) determining the interactions between these proteins in normal and pathological conditions. Identifying new players in NMD diseases is of major importance, not only for molecular diagnosis and genetic counselling of families affected with these diseases, but also toward understanding the role of normal and mutant proteins in muscle and peripheral nerve. These genes can be viewed as the result of a functional screen revealing crucial players in the biology of muscles or nerves, the interaction between nerves and muscle or between Schwann cell and neurons.
For years, neuromuscular disorders have been considered as incurable diseases, however for fifteen years several proof of concept (PoC) have emerged and rise new hope for patients. The research group “Biotherapies targeted to neuromuscular disorders “, directed by Marc Bartoli aims to develop innovative therapeutic approaches for different neuromuscular diseases. The “Biotherapies targeted to neuromuscular disorders” group rely on a strong expertise obtained during the past years, in particular M. Bartoli contributed in the establishment of seven PoC that demonstrate the feasibility of several approaches for three distinct neuromuscular diseases and participated in clinical trials. This group will be closely linked to activities of the two other groups constituting the NeuroMyology team in particular by valorizing studies of patients presenting with extreme phenotype.
In particular, we develop novel therapeutic approaches, based on particular clinical observations and mutational data from our large cohort of patients. We will pursue our previous work towards further preclinical testing of therapeutic strategies developed by our group in particular: transcript rescue strategies (Exon skipping/Trans-splicing…).
Besides these transcript rescue strategies, we will also develop gene transfer strategy. We also advance “classical” pharmaceutical therapeutic approaches to neuromuscular diseases, under the condition that pharmaceutical targets are identified based on the molecular pathophysiology.
Finally, we intend to define the best strategy using preclinical models to assay efficacy of considered approaches to alleviate neuromuscular diseases. Ultimately, if some approaches are successful, they may lead towards translational strategies and we will further establish partnerships at national and international level, to accelerate implementation of innovation. We will make sure that the process of design, development and validation of our therapeutic strategies will go through a process of clinical trial evaluation. This part of the project represents a strategic decision for the team with the objective of introducing the knowledge and collaborations for the translation of our pre-clinical research projects into the development of clinical trials. In this context, we envisaged to participate in clinical trials promoted by biotech/pharmacological companies before launching our own clinical trials.