Skip to main content
European Commission logo print header

Rewiring with biased signaling to override oxidative pathway defects for SEPN1-related myopathy therapy

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.

Coordinator

UNIVERSITE PARIS CITE
Net EU contribution
€ 196 707,84
Address
85 BD SAINT GERMAIN
75006 Paris
France

See on map

Region
Ile-de-France Ile-de-France Paris
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 196 707,84