Repairing SERCA1 with CFTR Correctors: Innovative Zebrafish Model for Brody Myopathy Therapy (RESTORE)

Brody disease is a rare skeletal muscle disorder due to the deficiency of SERCA1 protein, resulting from mutations of ATP2A1 gene. Sometimes, a mutation introduces minimal defects in SERCA1 that can affect the correct three-dimensional structure of the protein, but not its proper function. The protein, although functionally active, is recognized as damaged by cells and prematurely eliminated, thus depriving the cell of the SERCA1 specific function. We proposed a new pharmacological approach aimed “to repair” the defective protein. By means of small molecules named CFTR correctors (especially C17 compound), our aim is to promote the recovery of the correct structure and avoid elimination of SERCA1 protein. The absence of suitable animal model slackens studies on the development of new therapies. In a previous project, we have generated a new zebrafish line expressing defective but functionally active SERCA1 protein. In this project we aim to test in this model the efficacy of our therapeutic strategy. Moreover, using a computational approach we will try to clarify how C17 molecule corrects the defective SERCA1, repairing its structure.