REBOOST · Rewiring with biased signaling to override oxidative pathway defects for SEPN1-related myopathy therapy
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-05-01 → 2022-04-30
- EU contribution
- €196,708
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Rewiring with biased signaling to override oxidative pathway defects for SEPN1-related myopathy therapy
SEPN1-related myopathy (SEPN1-RM or SELENON-RM) is a rare, untreatable congenital muscle disease in which mutations of the SEPN1/SELENON gene impair the antioxidant and ER stress protection mechanisms and mitochondrial function. This ultimately leads to a significant loss of energy production in muscle cells. SEPN1-RM patients experience muscle weakness and fatigue leading to 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 for most types of congenital myopathy; this has hampered efforts in devising therapeutic strategies. We have focused on SEPN1-RM in this study as it is a model of a monogenic muscle disease which allows us to directly attribute any detectable changes in cells and signaling pathways to the primary gene defect without confounding factors. Our overall objectives to overcome the therapeutic development bottlenecks are: (1) to use patient-derived cell culture to establish a high-throughput readout of the defective bioenergetic output and (2) to test a treatment strategy by exploiting potential biased signalings, which bypass SEPN1 defects to restore cellular bioenergetics. The findings from this study could serve as a model paradigm which could be applied to accelerate therapeutic development in other muscle conditions (including age-related muscle degeneration as well as other congenital or metabolic myopathies) associated with overlapping defects in muscle metabolism and bioenergetic.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- UNIVERSITE PARIS CITE · ParisCoordinatorFrance
Links
Data: CORDIS, © European Union