Modeling Pompe Disease with Engineered Human Skeletal Muscle

Abstract available April 2020

Full text available upon request. Please contact chris dot zhou at duke dot edu

I will post the full text here once the work is published.

Pompe disease is a rare lysosomal storage disorder characterized by deficiencies in acid-alpha glucosidase (GAA). Despite ongoing research into the pathophysiology of the disease and attempts to develop new treatments, the underlying disease mechanisms are not completely understood. Through my research in the Bursac lab, I was involved with a project to engineer an improved model of Pompe Disease using tissue engineering. We engineered a 3D human skeletal muscle model using primary muscle cells derived from diseased and healthy patients. Our model recapitulated structural phenotypes of Pompe Disease such as lysosomal enlargement, functional phenotypes such as increased susceptibility to metabolic stress, and biochemical phenotypes such as elevated glycogen levels. We treated our diseased tissue model with standard enzymatic replacement therapy and observed glycogen clearance. Our model can serve as an in vitro screening tool for identifying novel medicines for Pompe Disease. As a proof of concept, we treated engineered skeletal muscle with adeno-associated virus encoding GAA to assess its therapeutic potential. Taken together, our work showcases the utility and versatility of engineered skeletal muscle tissues, both as a discovery tool to further our understanding of fundamental biology and as a powerful validation tool furthering the quest of engineer better medicines.

In addition to research, this thesis also provides an overview of the activities I performed to satisfy the 5 components of the Grand Challenges Scholars Program, including research, interdisciplinary curriculum, entrepreneurship, global, and service learning. A brief description is included for each of those facets and their connection to my Grand Challenge – Engineering Better Medicines.