A multitask lentiviral vector for ex vivo gene therapy of Duchenne Muscular Dystrophy

Thirty-five years after the identification of the dystrophin gene as the cause of Duchenne Muscular Dystrophy (DMD) patients still wait for an efficacious therapy. Myoblast, mesoangioblast (vessel-associated myogenic progenitors ) transplantation, gene therapy with Adenoviral and more recently Adeno-associated viral vectors, oligonucleotides and PTC124, did not show efficacy in clinical trials. We developed a cell therapy approach based upon transplantation of mesoangioblasts that appeared promising in pre-clinical models of DMD. However, in a first clinical trial, efficacy was minimal, possibly due to the age of the patients, selected for safety reasons, which resulted in very poor colonisation of dystrophic muscles by donor cells (< 1%). So we improved the transplantation protocol and developed a combination of cell and gene therapy: patient mesoangioblasts were corrected with a new lentiviral vector expressing two small RNA  with different molecular function in order to enhance therapeutic efficacy. In other words, we used the cells as Trojan horses because when they fuse with regenerating the small RNA enters neighbouring nuclei and corrects them, thus increasing dystrophin production to therapeutic level. However we know that efficiency drops when moving to patients and in this project we will build a more efficient and effective multi-task vector. We will test DMD mesoangioblasts corrected with the new vector in dystrophic, immune deficient mice, and in case of complete restoration of dystrophin production, of a normal morphology and function, will move to a clinical trial with intent to cure.