Zebrafish Model for Ultra-Rare Disease Treatment

The journey to uncover potential treatments for an ultra-rare human disease, XMEA (X-linked myopathy with excessive autophagy), has taken an unexpected dive into the world of zebrafish. This seemingly incongruous pairing is an illustration of the powerful intersection between genetics, innovative disease modeling, and the surprising utility of a common aquarium dweller.

A team led by Matthew Alexander, Ph.D., at the University of Alabama Department of Pediatrics’ Division of Pediatric Neurology, and Jim Dowling, M.D., Ph.D., at the Hospital for Sick Children in Toronto, Canada, have been using the zebrafish to explore the genetic underpinnings of XMEA. This disease, which has only been identified in 33 cases worldwide as of March 2024, progressively weakens the muscles and can have deleterious effects on the liver and heart.

The researchers’ journey began with a single Alabama boy’s genome, which revealed a mutation in the VMA21 gene, a known trigger for XMEA. This led to a collaboration with the UAB Center for Precision Animal Modeling (C-PAM), where an audacious plan was hatched: to create a preclinical model of XMEA in zebrafish.

Zebrafish, despite their humble appearance, offer several advantages for genetic studies. Their rapid growth, large clutch sizes, and ease of genetic manipulation make them an ideal candidate for modeling human diseases. Moreover, their transparency as larvae provides a unique window into their internal biology.

By mutating the fish gene analogous to VMA21, Alexander and Dowling successfully created a zebrafish model of XMEA. Their findings, published in EMBO Molecular Medicine, reveal that their mutant zebrafish exhibited weakened muscles and other symptoms reflective of human XMEA.

This pioneering work not only confirms the utility of zebrafish in modeling rare diseases like XMEA but also showcases the potential of this approach in drug screening. Utilizing their unique zebrafish model, the team was able to test 30 clinically approved drugs, identifying two that significantly alleviated XMEA symptoms in the fish.

The team is now extending their research into mammalian models, studying the VMA21 mutation in mice to further advance our understanding and progress towards a viable clinical treatment.

This zebrafish study encapsulates the disruptive potential of synthetic biology and precision medicine. It underscores the power of interdisciplinary collaboration in tackling rare diseases and the value of venturing into uncharted waters (literally, in this case) in the quest for novel therapeutic solutions.

As we move forward, the zebrafish, this unexpected hero of biotech, continues to serve a critical role in our understanding of genetic diseases. The story of its contribution to the fight against XMEA is a testament to the creativity, audacity, and relentless drive of the biotech industry to push boundaries and bring hope to those afflicted with rare diseases.