Periodic Reporting for period 1 - REBOOST (Rewiring with biased signaling to override oxidative pathway defects for SEPN1-related myopathy therapy)
Período documentado: 2020-05-01 hasta 2022-04-30
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.
We have also performed an unbiased analysis of the SEPN1-RM patient-derived cells RNA expression and revealed a defect in a major pathway which regulates cellular bioenergetics. This defective pathway was also independently identified in SEPN1-RM patient muscle cell cultures using single-cell mass cytometry. To validate this finding, we treated SEPN1-devoid human cells with a known agonist acting on this pathway and found that treatment was efficacious in restoring the ATP (bioenergetic) content to a level comparable to that of the controls.
We communicated with our university (University Paris Cité) to evaluate the potential commercial values from our findings including the implementation of our ATP-HTS as diagnostic tool. In addition, we have uncovered a robust effect of a known agonist drug acting on a compensatory signaling pathway which enhances patient’s bioenergetic level and might represent a first treatment for this (and other related) inherited muscle disease. We are exploiting this finding as potential therapy for SEPN1-RM and submitting the provisional patent to protect it through the Erganeo team, our Technology Transfer and Innovation office of the University Paris Cité.