2025 Annual Report

a failure to acidify, and the muscle cells had characteristic vacuoles — fluid-filled enclosed structures. Like human XMEA patients, the fish also showed liver and heart pathologies. Unlike human XMEA, which can vary from mild to moderate symptoms as a progressive disease, the mutant fish showed severe reductions in life span, presumably due to a more complete loss of VMA function compared to human patients. Since the fish had impaired autophagy and since there are no therapies for XMEA patients, the researchers tested 30 clinically tested autophagy inhibitory compounds from the Selleckchem drug library on the XMEA fish. RESEARCH RESEARCH “The fact that multiple autophagy modulators ameliorated aspects of the phenotype […] lends con dence to the validity and potential translatability of the ndings to patients” MATTHEW ALEXANDER, PH.D. Screening of clutches for changed muscle birefringence, a change in the refraction of polarized light that indicates reduced muscle organization, the team identified nine compounds that both reduced abnormal birefringence and prolonged fish survival. Long-term testing of the nine for improvements in survival and swimming showed that edaravone and LY294002 had the greatest therapeutic effects. “Excitingly, we found that several autophagy antagonists could ameliorate aspects of the VMA21 zebra sh phenotype, and two compounds in particular improved the phenotype across multiple domains of birefringence, motor function and survival,” Alexander said. “The fact that multiple autophagy modulators ameliorated aspects of the phenotype supports an important role for autophagy in the disease process and lends con dence to the validity and potential translatability of the ndings to patients.” ●

Co-authors with Alexander and Dowling in the study “X-linked myopathy with excessive autophagy: characterization and therapy testing in a zebra sh model,” are Lily Huang, Rebecca Simonian and Lacramioara Fabian, Hospital for Sick Children; and Michael A. Lopez, Muthukumar Karuppasamy, Veronica M. Sanders and Katherine G. English, UAB Department of Pediatrics, Division of Pediatric Neurology. XMEA stands for X-linked myopathy with excessive autophagy. This work is supported in part by the Center for Precision Animal Modeling (C-PAM), an NIH-funded initiative led at UAB by Bradley Yoder, Ph.D., chair of the Department of Cell, Developmental and Integrative Biology, and Matt Might, Ph.D., Hugh Kaul Endowed Chair of Precision Medicine and director of the Hugh Kaul Precision Medicine Institute.

86

CHILDREN’S OF ALABAMA | UAB MEDICINE