Developing treatment strategy for RBCK1 defect in patients’ derived stem cell models

Disease due to genetic mutations in RBCK1 is characterized by the development of progressive muscular weakness and cardiomyopathy and can lead to death in the second decade of life. Aggregates of proteins and branched glycogen molecules accumulate in the affected tissues and replace the normally structured glycogen. The role of the protein encoded by RBCK1 in the cell and in particular in the glycogen metabolism is not clear, and what leads from the genetic defect to the accumulation of polyglucosans is not known. In our project, we will try to answer these questions by generating and studying stem cells from fibroblasts obtained from RBCK1 patients. These two-dimensional and three-dimensional models of skeletal muscle and cardiomyocyte stem cells will be used to experiment a gene editing with CRISPR/Cas9 technology and to evaluate the efficacy of therapies currently approved by the FDA for other pathologies, but which could also be useful in RBCK1 disease. The compound that will be effective and safe in modifying the altered metabolism of glycogen and reducing protein aggregates will be tested in a clinical trial for human use.