From unknown diagnosis to new treatment, a UAB C-PAM discovers pathway towards new treatments for an ultra-rare myopathy

The journey from diagnosis to treatment can be long and arduous, especially for ultra-rare conditions. One such condition, X-linked Myopathy with Excessive Mitophagy (XMEA), has recently seen promising developments thanks to the pioneering efforts at the University of Alabama at Birmingham (UAB) within the UAB Center for Precision Animal Modeling (CPAM).

The story begins with cousins who are affected by an undiagnosed myopathy, a disease that affects skeletal muscles. Their late grandfather suffered from a similar condition as does the younger cousin who is 4 years younger, and through family history and whole exome sequencing (WES) it was determine a pathogenic variant in the X-linked VMA21 gene, a known cause of X-linked Myopathy with Excessive Mitophagy (XMEA). XMEA is classified as an ultra-rare myopathy as of March 2024; 24 cases have been worldwide identified. No suitable animal model existed to identify treatments for their ultra rare myopathy. Dr. Michael Lopez of UAB Pediatric Neurology referred the cousins to UAB CPAM, whom accepted the case with the goal(s) of establishing new animal model(s) including patient-specific VMA21 versions of the XMEA disorder in zebrafish and mice, to promote research and identify new treatments.

Given the lack of suitable animal models for XMEA, the UAB CPAM took on the challenge of creating patient-specific models in zebrafish and mice. As part of the outreach process, we contacted Dr. Jim Dowling (U. Toronto/SickKids Hospital) who had previously mentioned both an interest in XMEA and had begun to generate vma21 mutant zebrafish in parallel. Through a mutual collaboration, the lab of Matthew Alexander (UAB/CoA; CPAM DSS co-lead) began to characterize the vma21 mutant fish generated by the Dowling lab while generating the XMEA patient-specific Vma21 mutant zebrafish and mouse models.

Through extensive molecular and functional characterization, the CPAM team developed several new zebrafish zebrafish and a new patient-specific VMA21 knock-in (Vma21 KI) XMEA models. A targeted drug screening performed by the Alexander lab in the vma21 mutant (complete loss-of-function) zebrafish identified a class of autophagy inhibitors, including edaravone (Radicava®), an FDA-approved oxidative stress drug for amyotrophic lateral sclerosis (ALS). Short and long-term testing in the XMEA vma21 mutant fish showed improved muscle pathologies, improved functional outcomes, and extension of survival. The XMEA Vma21 KI mice have a milder pathology as this model variant more closely resembles the Alabama patient identified.

The long-term goal is to perform additional safety testing of these FDA-approved drug compounds in the Vma21 KI mice as verifying drug efficacy in two models of XMEA would demonstrate a new drug pathway and target, giving hope to both this Alabama family and others worldwide dealing with this devastating disorder. Demonstrating drug efficacy in both zebrafish and mouse models could pave the way for new treatments, offering hope to families affected by XMEA worldwide.