Gene editing in Myotonic Dystrophy type 1: assessment of efficiency, safety and therapeutic effect of CTG-repeat deletion in a mouse model of disease.

Myotonic dystrophy type 1 (DM1) is a hereditary disorder involving many different body organs; symptoms include myotonia, muscle weakness, heart defects, eye cataract and neurological dysfunction. DM1 is caused by a genetic defect consisting in abnormal repetitions of three nucleotides (CTG) in the DMPK gene, which encodes for a myosin kinase particularly expressed in muscle and nerve tissue. DM1 disorder results from the toxicity of the defective RNA molecules produced by the DMPK gene that acquire abnormal localization and function within the cell nucleus. In cells from DM1 patients, the defective RNA is accumulated into characteristic spots called nuclear foci and therefore cannot be translated into protein. In addition, these RNA molecules sequester into nuclear foci important proteins involved in regulation of the maturation process of most cellular RNAs. To date, no specific treatments are available for DM1. Our project focuses on the application of a gene therapy approach in an animal model of DM1, that leads to the permanent elimination of the genetic defect. This will be possible by means of a recently developed powerful technology, designed to eliminate specifically the defective DNA regions and restore the normal gene function. By using this strategy we have already removed successfully the genetic defect in cells from DM1 patients. Our research will allow to progress from in vitro studies to in vivo application, a necessary step to acquire the essential preclinical efficacy and safety data for future application in humans.