Background on Danon Disease Danon disease is a rare X-linked dominant genetic disorder with an incidence of fewer than 1 in 1 million individuals worldwide. It is caused by mutations in the LAMP2 gene, which plays a crucial role in lysosome function. Loss of LAMP2 gene function causes impaired cellular waste recycling – ultimately manifesting in clinical features such as muscle weakness, cardiomyopathy, intellectual disability, and liver disfunction. There is no cure for Danon disease. The disease progresses until a heart transplant is required or death occurs. LAMP-2B is the predominant isoform form in humans and is required for lysosomal activity in cardiomyocytes. Loss of LAMP-2B function is sufficient to drive phenotypes observed in cardiomyocytes of those afflicted with Danon Disease. Importantly, loss of the other LAMP-2 isoforms (LAMP-2A, LAMP-2C) is NOT sufficient to induce a Danon Disease phenotype in cardiomyocytes.
Gene Therapy for Danon Disease The Song Lab developed a gene therapy via CRISPR editing targeting the LAMP-2B mutation that restores autophagy, mitochondrial function, and improves contractility of induced cardiomyocytes (iCM) derived from Danon patient pluripotent stem cells.
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