Enhancement of extravasation and fusion factors to enable cellular therapy for Muscular dystrophies
Background
Muscular dystrophies are incurable diseases for which cell-based therapies present a promising therapeutic option. While the root cause of all muscular dystrophies is genetic, gene therapy alone cannot reverse existing muscle degeneration, especially in aged patients where muscle wasting is widespread. Complete reversal of muscle damage requires replacing diseased muscles with new healthy ones, potentially achievable through the transplant of muscle stem cells. However, progress may be hindered by the low rate of cell extravasation from the circulatory system involved in systemic delivery and the inability of cells to fuse with existing muscle fibers.
Technology Overview
Researchers at Boston Children’s Hospital aim to enhance cell extravasation and muscle cell fusion by identifying genes that influence these processes using CRISPR technology. They employed CRISPR libraries to identify and edit genes essential for cell fusion and/or extravasation in each cell population. By introducing inhibitory nucleic acid molecules, such as antisense oligonucleotides, short interfering RNA (siRNA), or small hairpin RNA (shRNA), they targeted and suppressed specific genes that inhibit extravasation or fusion. Similarly, by introducing expression vectors encoding specific genes into isolated cells and overexpressing these genes, the cells can be engineered to have enhanced capabilities for extravasation and fusion.
The engineered cells, either lacking certain inhibitory genes or overexpressing enhancing genes, can be used in cell transplantation therapies for more efficient treatment and improved outcomes in muscle cell transplantation.
Applications
- Treatment of Muscular Dystrophies
Advantages
- Increased successful delivery and fusion of transplanted muscle cells
- Ability to reverse existing muscle degeneration
Publications
Lek, A., Zhang, Y., Woodman, K. G., Huang, S., DeSimone, A. M., Cohen, J., Ho, V., Conner, J., Mead, L., Kodani, A., Pakula, A., Sanjana, N., King, O. D., Jones, P. L., Wagner, K. R., Lek, M., & Kunkel, L. M. (2020). Applying genome-wide CRISPR-Cas9 screens for therapeutic discovery in facioscapulohumeral muscular dystrophy. Science translational medicine, 12(536), eaay0271. https://doi.org/10.1126/scitranslmed.aay0271
