Anne Buckley, MD, PhD, published an article in the April 2023 issue of the Journal of Neuropathology & Experimental Neurology (JNEN) titled “Outside the Fiber: Endomysial Stromal and Capillary Pathology in Skeletal Muscle May Impede Infusion Therapy in Infantile-Onset Pompe Disease.”
Since the discovery of an effective enzyme replacement (ERT) for Pompe disease in the early 2000’s, a disease that predictably killed children in their first year of life has become manageable, with the first generation of fully treated patients now in their teens. However, although early deaths from cardiac and respiratory failure are no longer inevitable, fully treated patients still suffer from motor deficits, suggesting that skeletal muscle does not respond well to ERT even when infusion therapy is started at birth.
In a multi-year study of pediatric Pompe patients receiving ERT, Buckley and colleagues discovered that at least part of the problem lies outside the muscle fibers, in the stroma and blood vessels around them. Glycogen and cellular material released from fibers into the stroma induces fibrosis and other reactions that inhibit movement of infused ERT from the bloodstream to the muscle fibers, acting as a mechanical barrier to treatment. This discovery was made possible by electron microscopy, which remains the only way to precisely examine individual tissue components and their relationships.
The article describes results from her collaboration with colleagues Maureen Petersen, Januario (Henry) Estrada, and Justin Waterfield from Duke’s Clinical Electron Microscopy Laboratory; her mentor Professor Emeritus of Pathology Edward Bossen, MD; and clinical colleagues in Duke’s Department of Pediatrics and Medical Genetics led by Priya Kishnani, MD, one of the main developers of modern ERT for Pompe disease.
This research will inform the development of specific adjunct therapies to overcome these barriers to treatment, which have been made visible by the unique capabilities of electron microscopy.
Buckley is an assistant professor of pathology and a member of the Preston Robert Tisch Brain Tumor Center. She is also involved in translational and basic research on brain, muscle, and kidney disorders with other research groups at Duke.