Stem cell and gene therapies

Assessing the therapeutic potential of stem cell and gene therapies to remedy muscle diseases

Our laboratory is dedicated to evaluating the clinical applicability of myogenic stem cells and gene therapies for the treatment of muscle diseases. In particular, our objective is to use induced myogenic progenitor cells (iMPCs) to remedy rodent models for Duchenne muscular dystrophy (DMD), the most common muscular dystrophy in humans. In our recent research, we reprogrammed fibroblasts from two DMD mouse models into iMPCs that lacked dystrophin expression and demonstrated their expansion and differentiation capacities. Leveraging the CRISPR-Cas9 gene editing system, we corrected the dystrophin mutation in DMD-iMPCs, most notably in their stem cell subset. Furthermore, we showed that corrected iMPCs engrafted limb muscles, fused with dystrophic fibers, restored dystrophin expression in vivo, and contributed healthy muscle stem cells to the satellite cell reservoir. These findings present a novel in vitro model for DMD, and highlight the translational potential of iMPCs for treating this debilitating condition (external pageDomenig et al., Stem Cell Reports, 2022call_made). Additionally, we recently developed a method to produce safer and more clinically relevant iMPCs with enhanced transplantation potential, capable of restoring dystrophin expression in a dystrophic mouse model. This innovative approach involves repeated transfection with MyoD-mRNA, coupled with an augmented compound cocktail identified through a small molecule screen (external pageQabrati et al., NPG Regen Med, 2023call_made). Our ongoing efforts include the exploration of new techniques to enhance the in vivo transplantation potential of muscle stem cells, in addition to assessing whether in vivo myogenic reprogramming can be harnessed for the treatment of muscle pathologies such as fibrosis. Furthermore, we are actively employing novel genome editing tools, including Base and PRIME editing, to correct mutations responsible for various muscular dystrophies. Collectively, these combined efforts represent strides towards advancing the field of stem cell and gene therapies for the treatment of muscle diseases.