Project description
Rewiring signalling to find therapy for SEPN1-related myopathy
Selenoprotein-related myopathy (SEPN1-RM) is a rare untreatable congenital myopathy in which SEPN1 mutations impair the antioxidant system and mitochondrial oxidative function, leading to a significant loss of bioenergetic production and muscle cell functions, potentially lethal respiratory failure and mobility impairment. The EU-funded REBOOST project aims to use patient-derived cells to establish high-throughput readouts of metabolism, facilitating drug repurposing for SEPN1-RM, and employ original treatment strategies exploiting signallings bypassing SEPN1 defects to restore cellular bioenergetics. This study will facilitate the establishment of SEPN1-RM biomarkers and novel therapeutic studies, and provide a model approach for the analysis and treatment of other inherited or acquired myopathies sharing an underlying bioenergetic deficiency, including sarcopenia and cancer cachexia.
Objective
SEPN1-related myopathy (SEPN1-RM) is a rare, untreatable debilitating congenital myopathy in which SEPN1 mutations impair the antioxidant system, ER stress protection and mitochondrial oxidative function. These altered cellular processes ultimately lead to a significant loss of bioenergetic production and abrogate muscle cellular functions. SEPN1-RM patients experience potentially-lethal respiratory failure and major life burden due to loss of mobility. Currently, there are no high-throughput or appropriate preclinical models to facilitate identification of disease-modifying drugs; this has hampered efforts in devising therapeutic strategies. To overcome these bottlenecks, I aim to use patient-derived cells to establish (1) high-throughput measureable readouts of metabolism, facilitating repurposed drug screen for SEPN1-RM; (2) an original treatment strategy by exploiting potential biased signalings, which bypass SEPN1 defects to restore cellular bioenergetics. I will capitalize on (1) the availability of SEPN1-RM biopsies, (2) host lab expertise for handling and culturing primary SEPN1-RM cells and (3) my experience in muscle biology and innovative tools for analysing metabolic/signalling pathways. I aim to implement transcriptomic analyses by using next-generation RNA-seq, optogenetic based sensors to quantify metabolic activity, real-time clonal analysis of cell fate with dynamic fluorescent time-lapse microscopy and multi-dimensional assessment of intracellular activities at single-cell level via CYTOF technology. This study will not only facilitate the establishment of SEPN1-RM biomarkers and novel therapeutic studies, it will also provide a model paradigm for analysing and treating other inherited or acquired myopathies sharing an underlying bioenergetic deficiency, including sarcopenia and cancer cachexia.
Fields of science
Not validated
Not validated
Programme(s)
Funding Scheme
MSCA-IF-EF-ST - Standard EFCoordinator
75006 Paris
France