Therapeutic Drug Discovery using Fish Models of Muscular Dystrophies
The muscular dystrophies are a heterogeneous group of genetic disorders for which there are now emerging therapies. Despite these advances, there are only a few small molecules that can modify muscle disease. Zebrafish represent an excellent model in which to test for small molecules that can alter disease progression in a live organism. Our laboratory and collaborators have some excellent fish models of the human muscular dystrophies. Each fish has clear muscle phenotype due to a gene mutation in a muscle membrane protein, a muscle extracellular matrix and a muscle intracellular protein. 1) Sapje and sapje-like fish are the model fish of DMD with a mutation in the dystrophin gene 2) Dystroglycan deficient fish are a model fish for dystroglynopathies. Dystroglycan is a muscle membrane protein consisting of α- and β-dystroglycan, which interacts with dystrophin and extracellular laminin 3) Laminin α2 mutant fish are a model fish for congenital muscular dystrophy 1A (MDC1A). The laminin α2 gene is expressed in the basement membrane of skeletal muscle and has been shown to bind to α-dystroglycan. We have already successfully screened three libraries using two DMD model fish, sapje and sapje-like fish. Through this chemical screen, we have identified 14 candidates chemicals that demonstrated an ability to partly restore muscle to normal. The goal of this proposal is to test these potentially therapeutic small molecules already approved for use in humans to determine if any can ameliorate muscle degeneration in zebrafish models of human muscular dystrophy. We will also use each two additional model zebrafish to look for new small molecules which might be corrective.