The HUMANiSM proposal aims to establish mature human neuromuscular junction (NMJ) in vitro models representative of different neuromuscular diseases (NMD) and to develop new screening tools for drug discovery approaches driven by academia and industry. NMD correspond to a vast group of diseases that perturbs or even progressively blocks the control and the force of muscle voluntary movement by affecting motoneurons and NMJs. To date, no efficient curative treatments have been identified for NMD. Progresses towards identification of new treatments have been hampered by the incomplete understanding of the molecular mechanisms that control synapse formation and maintenance as well as the availability of relevant screening tools. Indeed, to date research in NMD field are facing several challenges: (1) difficulty in examining the NMJs of patients with NMD, and absence of reliable biomarkers revealing disease status and evolution, (2) lack of reliable in vitro models recapitulating functional human NMJ, (3) animal models poorly phenocopy the human diseases because of genetic and physiological discrepancies between the neuromuscular systems of mouse and man, (4) in vivo models are complex to analyze and do not allow the study of each partner cell at the synapse. Altogether, these bottlenecks largely block the deployment of drug discovery campaigns and therefore abrogate the development of new medicines curing NMD early on in the drug development process.
In this context, HUMANiSM consortium propose to first generate a model of in vitro human mature NMJs fully compatible with High Content Screening approaches then to establish pathological models of representative NMD diseases. While developing these models, our proposal has several objectives (1) to decipher the pathophysiological mechanisms of human NMJ formation, (2) to use biomarkers revealed by the mechanistic approach as readouts for drug screening and (3) to validate these development by a proof of concept screening and (4) to convert these models into marketable products. Ultimately, our aim is to deliver a series of meaningful models that will accelerate our understanding of NMJ diseases while ensuring its direct availability to academic lab or pharmaceuticals companies for screening campaigns.
To achieve these goals, the consortium has secured all the necessary expertise and relies on solid preliminary results. Indeed, Partner 1 and Partner 3 (Claire Legay, Paris Descartes and Laurent Schaeffer, ENS Lyon) are leading experts in deciphering molecular mechanisms involved in normal and pathological NMJ formation. Partner 2 (Ce´cile Martinat, I- STEM, Paris) was one of the first laboratory developing disease-specific human motoneuron- muscle co-cultures with muscle cells to study pathologies and applications for large scale phenotypic screening. Partner 4 (Yoran Margaron, CYTOO) brings an industrial expertise in the development of pertinent cellular model compatible with large scale phenotypic screening. Partner2 and 4 have already successfully established co-culture conditions between spinal motoneurons (MN) from Human induced Pluripotent Stem Cells (iPSC) and human muscle cells to form numerous NMJs, a cell model which is the basis of all planned development.
The proposed project offers a genuinely innovative opportunity to push beyond the limitations of current models and promises to open up major new “assay development space” by increasing our understanding of the NMJ, identifying disease specific biomarkers and offering a platform that can be applied to a wide range of research areas. While our focus carries risks, we expect to deliver more meaningful, broadly-applicable and longer-lasting advances for the NMJ community. By focusing on such enabling technologies, which have a potentially huge impact and where SMEs can play a fundamental role, HUMANiSM will give participating partners a leading edge in the long term.
Madame Claire Legay (Centre de Neurophysique, Physiologie,Pathologie)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
UNIV-LYON1 Laboratoire de Biologie Moléculaire de la Cellule
CNRS Centre de Neurophysique, Physiologie,Pathologie
INSERM Inserm - Istem U861
Help of the ANR 590,000 euros
Beginning and duration of the scientific project: September 2015 - 36 Months