Bipotential progenitor cells to treat cardiac and skeletal muscle degeneration in a large animal model of Duchenne Muscular Dystrophy.

Duchenne Muscular Dystrophy (DMD) causes untreatable and progressive degeneration of cardiac and skeletal muscles. Cell therapies are emerging as curative approach to functionally regenerate damaged muscles, yet strategies to equally target both muscle types are still missing. Induced pluripotent stem cells (iPSCs) are raising new expectations in the field, given the unprecedented possibility of patient-matched cells virtually differentiating into all tissues. Interestingly, the efficiency of iPSC differentiation can be enhanced by the epigenetic memory, namely the complex of epigenetic biases inherited from source cells. We have previously combined iPSC technology and epigenetic memory to develop bipotential injectable progenitors, able to engraft and functionally regenerate both heart and skeletal muscles of dystrophic mice. However, it is still a compelling question whether this dual approach is translatable from bench to bedside. Therefore, in this project we will thoroughly address this question in Golden Retriever dogs affected by Muscular Dystrophy, the foremost large animal model for DMD. We will assess the in vivo capacity of canine bipotential progenitors in heterologous therapy of cardiac and skeletal muscles. Moreover, we will provide a proof-of-principle of genetic mutation correction and autologous therapy. Finally, we will challenge the translational relevance of this approach by testing human bipotential progenitors in immunodeficient dystrophic mice.