Zebrafish Model Unveils Potential Drugs for Rare Genetic Disease XMEA

Researchers have developed a zebrafish model to study X-linked myopathy with excessive autophagy (XMEA), an ultra-rare genetic disorder that causes progressive muscle weakness and can involve liver and heart complications. This disease, with only 33 cases documented worldwide as of March 2024, is caused by mutations in the VMA21 gene.

In collaboration between the University of Alabama at Birmingham and the Hospital for Sick Children in Toronto, scientists created a zebrafish model by targeting the fish gene analogous to VMA21. Zebrafish are valuable in disease research due to their rapid development, large offspring numbers, and transparent embryos, facilitating genetic studies.

The mutant zebrafish exhibited symptoms mirroring human XMEA, including muscle weakness, shortened body length, reduced swim capacity, and cellular markers such as lysosomal failure to acidify and muscle vacuoles. These models allowed the team to test 30 drugs previously approved for clinical use, identifying two—edaravone and LY294002—that significantly improved muscle function and survival.

Since autophagy impairment is central to XMEA pathology, drugs targeting this pathway were evaluated. The positive findings suggest that modulating autophagy could be a therapeutic strategy for the disease. Currently, efforts are underway to investigate these promising compounds in mouse models to pave the way for potential clinical applications.

This study marks a crucial step in understanding XMEA and highlights the potential of zebrafish models in rare disease research, offering hope for therapeutic developments in this debilitating condition.