Neuromuscular diseases correspond to a vast group of disorders that collectively affect 160 per 100,000 people worldwide. Despite recent progresses, a large proportion of these diseases still do not have definitive treatments. Progresses towards identification of new treatments have been hampered by the availability of relevant screening tools as well as the incomplete understanding of the pathogenic mechanisms although the causative mutations and genes for these diseases have been identified. Indeed, to date the success rate for identifying therapeutics that reaches the market is extremely low. Most drug candidates were withdrawn at various stage of the discovery and development process for reasons as safety or formulation issues, poor ADME properties and lack of efficacy in the clinic. Several parameters can explain this high rate of attrition: (1). The use of disease non-relevant cellular models for drug screening campaigns; (2). The use of target-based drug discovery approaches in which the starting point is a defined molecular target hypothesized to play a pivotal role in the disease. Therefore, one of the most important challenges for the future identification of new therapeutics will depend on establishing more predictive translational models capable to capture the biological complexity of the disease.
This applies in particular to Myotonic Dystrophy Type 1 (DM1). This inherited disease is the most common form of muscular dystrophy in adult for which the causal mutation has been identified thirty years ago. Despite major efforts made to generate therapeutic strategies designed to target the molecular substrates associated to this disease, none of them was successful so far and there is currently no cure for this disease. Development of an effective therapeutic approach for DM1 is confronted with a major challenge due to its complex physio-biology. This example illustrates the needs to implement innovative strategies for the discovery and development of new medicines relying on more predictive translational models capable to capture the biological complexity of the disease.
In this context, the TREAD consortium proposes to develop unbiased screening approaches using stem cell-based disease models that promise to more realistically recapitulate the complex biology of the disease. Thus, this proposal will focus on myogenic defects observed in DM1 patients that can be reproduced in vitro by using skeletal muscle cells derived from DM1. The TREAD consortium will combine the use of disease-specific human stem cells differentiated into relevant cell types with informative high-content imaging screening based on multiparametric approaches and artificial intelligence to identify new therapeutic. Overall, our proposal has several objectives (1) identify and optimize new myogenic inductors compounds capable to normalize the myogenic defects associated with DM1, (2) decipher their mode of action (3) validate their action in vivo and (4) deliver a meaningful technology that will accelerate the development of therapeutics for the growing list of neuromuscular diseases. Ultimately, our aim is to convert the best lead candidate identified by this technology into clinical and marketable products.
Finally, our proposal 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 the mechanisms that affect DM1 skeletal muscle, identifying disease specific modulators and offering a platform that can be applied to a wide range of research areas. By focusing on such enabling technologies, which have a potentially huge impact and where industrials can play a fundamental role, TREAD will give participating partners a leading edge in the long term.
Madame Cécile MARTINAT (INSTITUT DES CELLULES SOUCHES POUR LE TRAITEMENT ET L'ETUDE DES MALADIES MONOGÉNIQUES)
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.
Centre de Recherche en Myologie
I-STEM INSTITUT DES CELLULES SOUCHES POUR LE TRAITEMENT ET L'ETUDE DES MALADIES MONOGÉNIQUES
Help of the ANR 603,870 euros
Beginning and duration of the scientific project: December 2021 - 36 Months