Brody Disease: A Novel Zebrafish Animal Model to Test Potential Therapeutic Approach for This Rare Human Disease

Brody disease (BD) is a rare genetic disorder characterized by exercise-induced muscle stiffness and impairment of relaxation. Bovine pseudomyotonia (PMT) is a genetic muscular disorder depicted as the true counterpart of BD in mammals. Missense mutations in the ATP2A1 gene, encoding Sarco(Endo)plasmic ReticulumCa2+-ATPase isoform1 (SERCA1), cause BD in humans and PMT in cattle. At present, neither specific therapy nor mouse model for BD exists. Recently we have proposed an innovative pharmacological approach based on the use of protein folding correctors known as CFTR (Cystic Fibrosis Transmembrane Regulator) explored in Cystic Fibrosis. We have already established in-vitro and in-vivo (local muscle treatment of PMT-affected cows) the efficacy of C17 corrector to restore the expression level of mutated SERCA1. However, large animals aren’t suitable for drugs systemic administration and bovine PMT as BD, is a rare genetic myopathy. Because of the absence of the ideal mouse model we decided to use the commercially available natural mutant Zebrafish Accordion, carrying S766F SERCA1 mutation as an indispensable tool to confirm the efficacy and safety of our new therapeutic strategy. At the same time, we manipulated the zebrafish genome with the CRIPSR/Cas9 technology to generate mutant line carrying SERCA1 mutation found in bovine PMT. We affirmed the eligibility of this zebrafish mutated line as a new animal model of human Brody disease. Our aim is to translate into therapy the use of CFTR C17 small molecule to cure defective but functional SERCA1 proteins, causing BD in humans.