Drosophilaas a starting point for developing therapeutics for the rare disease Duchenne Muscular Dystrophy

Abstract

Progress into developing therapeutics for rare diseases can be accelerated for those diseases that can be modeled in genetically tractable organisms. Here we comment on one disease, Duchenne Muscular Dystrophy (DMD), modeled in Drosophila that brought together disparate lines of research toward the goal of developing a therapeutic. Though the bioactive lipid sphingosine 1-phosphate (S1P) has been implicated in many anabolic processes in many cell types and tissues, including muscle, this work confirmed the therapeutic potential of assessing this pathway for DMD. Genetic dissection of sphingolipid metabolism showed the suppression of muscle structural and functional defects in flies. Moreover, improvement of muscle defects using known pharmacological agents that raise S1P levels in vivo highlight the potential of Drosophila as a drug-screening tool for DMD. We and others have extended S1P studies into the mouse model of DMD and have shown a partial amelioration of symptoms associated with DMD. Translation of this work to mammals makes the sphingolipid metabolism pathway a promising target for further drug development that may benefit the human condition.

Transgenic Drosophila for Investigating DUX4 and FRG1, Two Genes Associated with Facioscapulohumeral Muscular Dystrophy (FSHD)

“…Informative Drosophila models have been generated for several neuromuscular diseases and for six of the nine classes of muscular dystrophy including Duchenne [ 58 , 61 ], myotonic [ 57 , 102 ], congenital, including certain dystroglycanopathies [ 58 , 59 , 103 , 104 ], Emery-Dreyfus [ 60 , 105 ], oculopharyngeal [ 56 ], and limb-girdle [ 54 ]; however, no Drosophila model for FSHD based on any candidate gene has been reported. Therefore, the Drosophila lines presented here that will allow investigations into the functions of two genes important to FSHD and will fill an important void in FSHD research by providing valuable resources for those studying muscle development and FSHD.…”

“Betwixt Mine Eye and Heart a League Is Took”: The Progress of Induced Pluripotent Stem-Cell-Based Models of Dystrophin-Associated Cardiomyopathy

“…To recapitulate MD, different mutations in Dys were generated in D. melanogaster that show mobility defects, age-dependent muscle degeneration, and neuronal and circulatory defects [ 263 , 264 , 265 ]. This model was also used to screen different phenotype ameliorating compounds [ 266 ].…”

S1P/S1P Receptor Signaling in Neuromuscolar Disorders

“…Studies in Drosophila, which does not have identified S1PRs, have shown that genetic increase of the levels of the S1P or delivery of the S1P lyase inhibitor THI suppresses dystrophic muscle degeneration [190]. In mice S1P can act as a ligand for S1PRs and as a HDAC inhibitor.…”