ANIMAL MODELS TO VALIDATE THE USE OF NEW SMALL SYNTHETIC TRANSCRIPTION FACTORS IN THE GENE THERAPY OF MUSCLE DYSTROPHIES

Our project is based on the construction of synthetic genes designed to up-regulate the expression level of utrophin, a protein very similar to dystrophin and able to replace the functions of defective dystrophin in Duchenne Muscular Dystrophy (DMD). Over-expression of utrophin gene represents one of the main therapeutic strategies proposed in the last years for the cure of Duchenne and Becker dystrophies. We designed and engineered a new transcription factor gene, named “Jazz” capable of binding and activating transcription from the promoter of the utrophin gene. With this gene we constructed a transgenic animal model expressing, in muscle, the artificial transcription factor “Jazz” that successfully up-regulated utrophin. Moreover we observed a significant recovery of muscle strength in dystrophic mdx mice crossed with our transgenic model. Starting from these positive results, we developed an even more specific and efficient four zinc finger transcription factor (“Bagly”) that will be used to create a new transgenic model of recovery from dystrophic damages and to test the feasibility and efficacy of a gene therapy of DMD based on these molecules.