The molecular portfolio of the extraocular muscles: keys to protection in muscle disease

The extraocular muscles (EOMs) are remarkably resistant to muscle dystrophies, despite having the same gene defect that affects all body muscles leading to severe handicap and premature death. Effective treatments of muscle dystrophies are currently completely lacking.

We have recently shown in a zebrafish model that ectopic expression of an EOM-origin protecting gene in body muscles can ameliorate a severe muscle dystrophy phenotype and prolong survival.

Here we propose to identify and evaluate additional candidate genes that protect the EOMs in muscular dystrophies; elucidate the molecular mechanisms behind them, with special emphasis on mechanosensing and to screen for small molecules to develop novel therapeutic options for muscle dystrophies based on these protective target genes.

We have developed several zebrafish muscle dystrophy models.

We use CRISPR/Cas9 mediated knockout and gene overexpression, along with RNA sequencing, qPCR, in situ hybridization, immunocytochemistry and any additional molecular biology methods needed along with functional tests, in zebrafish.

We validate gene expression patterns in human EOMs and limb muscle samples of both males and females.We are at an ideal position to analyze the role of putative target genes in EOM biology and in muscle dystrophies with the aim of providing novel therapeutic approaches leading to improved quality of life and improved survival for these patients.