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 and NEUROMICS), the MYOCAPTURE 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, Channelopathies), 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.
Inherited peripheral neuropathies (IPN) are one of the most frequent inherited causes of neurological disability characterized by extensive phenotypic and genetic heterogeneity. This group of neuromuscular disorders is distinguished by length-dependent progressive degeneration of the PNS. Based on clinical and electrophysiological properties, they can be subdivided into three main groups: Hereditary Motor and sensory Neuropathies (HMSN), also known as Charcot-Marie-Tooth disease (CMT), pure motor neuropathies (distal Hereditary Motor Neuropathies, abbreviated dHMN) and pure sensitive neuropathies (Hereditary Sensory Neuropathies, abbreviated HSN). Among IPN, CMT is the most common inherited disorder of the human peripheral nerve with a prevalence of 1 in 2500.
Our research group is dedicated toward unraveling the missing keys in genetics and physiopathology of Inherited Peripheral Neuropathies (IPNs) (mostly Charcot-Marie-Tooth disease (CMT)), in order to improve diagnosis and to set-up therapeutic strategies. This group of neuromuscular diseases is characterized by a strong genetic heterogeneity, with about 80 genes identified to date and all modes of inheritance described. These genes encode proteins of various functions in both axon and myelin. Beyond the major importance of gene identification in IPN in molecular diagnosis and genetic counselling of families affected with these diseases, the identification of defective genes in IPN is a major stimulus toward understanding the role of normal and mutant proteins in peripheral nerve, and in consequence the biology of myelin. These genes can be viewed as the result of a functional screen revealing crucial players in the interactions between Schwann cell and neurons. Studying how Schwann cell and axon-encoded proteins are functionally interconnected will provide crucial information about the interplay between SC and neurons. Moreover, comprehension of these processes is also crucial to identify targets for therapeutic interventions. In this context, we have several axes of research :
1) Identify new genes in IPN/CMT by studying large consanguineous families affected with rare autosomal recessive forms using a combination of homozygosity mapping and Next-Generation Sequencing (WGS/WES) and realize subsequent functional studies.
2) Understand the physiopathology of some CMT subtypes, in particular CMT4H, a rare autosomal recessive demyelinating form of Charcot-Marie-Tooth disease, for which we have described FGD4 as the culprit gene in 2007, using both cellular and animal models (mouse, zebrafish).
3) Develop a new human induced Pluripotent Stem Cells (hiPSC)-based in vitro model for the peripheral nerve system, in order both to assess the pathogenicity of the mutations identified in the genetic studies, and to dispose of a new tool for functional and preclinical therapeutic studies.
Using innovative approaches, we will identify new defective genes/proteins in NMD diseases. This group “Biotherapies Targeted to 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. These genes can be viewed as the result of a functional screen revealing crucial players in the biology of muscles, the interaction between muscle 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.