Abstract:
Muscular dystrophies are a diverse group of genetic diseases marked by progressive degeneration of skeletal and cardiac muscle. Despite extensive research into various therapeutic options, no definitive treatment has been developed for these debilitating conditions. Over the past thirty years, cell-based therapies have been explored experimentally. Several cell types, including myogenic stem and progenitor cells, stromal cells, and pluripotent stem cells, have been studied and have recently entered clinical trials with mixed outcomes. This review provides an overview of past efforts and the current status of cell-based therapies aimed at mitigating the skeletal and cardiac myopathy in dystrophic patients. It highlights the challenges, recent progress, and offers recommendations for future research and clinical trials.Major Points:
- Introduction to Muscular Dystrophies:
- Muscular dystrophies are a varied group of genetic disorders characterized by progressive muscle wasting and weakness. These arise from mutations in genes associated with various cellular components.
- Duchenne muscular dystrophy (DMD) is the most common and severe form, affecting approximately 1 in 5000 male newborns. It leads to progressive muscle weakness, respiratory problems, and cardiac involvement. Most DMD patients die in their third decade of life due to respiratory complications or heart failure.
- Becker muscular dystrophy (BMD) is a milder form, affecting about 1 in 20,000 male births. It has the same causative allele as DMD but presents later and has a longer life expectancy.
- Both DMD and BMD result from mutations in the DMD gene, which encodes the dystrophin protein. This protein is part of the dystrophin glycoprotein complex (DGC) essential for muscle functionality and integrity.
- Therapeutic Approaches:
- Current treatments, such as glucocorticoids, can slow disease progression, but there's no definitive cure for DMD and BMD.
- Various therapeutic strategies are under investigation, including gene delivery using viral or nonviral vectors, mRNA splicing alterations, and gene editing techniques like CRISPR/Cas9.
- The review emphasizes cell-based therapy, a method that has been explored for decades. This approach offers multiple promises: introducing normal gene copies into myofibers, supporting muscle repair, and delivering therapeutic benefits through cellular vehicles.
- Cell Therapy in Dystrophic Skeletal Muscle:
- Muscle stem cells (MuSCs), also known as satellite cells, are responsible for muscle regeneration. They have shown promise in promoting regeneration and repopulating the stem cell compartment.
- However, challenges like loss of potency during ex vivo expansion and limited in vivo migration after transplantation need to be addressed.