Glycogen storage disorders (GSDs) are inherited disorders of metabolism resulting from the deficiency of individual enzymes involved in the synthesis, transport, and degradation of glycogen. This literature review summarizes the development of gene therapy for the GSDs. The abnormal accumulation of glycogen and deficiency of glucose production in GSDs lead to unique symptoms based upon the enzyme step and tissues involved, such as liver and kidney involvement associated with severe hypoglycemia during fasting and the risk of long-term complications including hepatic adenoma/carcinoma and end stage kidney disease in GSD Ia from glucose-6-phosphatase deficiency, and cardiac/skeletal/smooth muscle involvement associated with myopathy +/- cardiomyopathy and the risk for cardiorespiratory failure in Pompe disease. These symptoms are present to a variable degree in animal models for the GSDs, which have been utilized to evaluate new therapies including gene therapy and genome editing. Gene therapy for Pompe disease and GSD Ia has progressed to Phase I and Phase III clinical trials, respectively, and are evaluating the safety and bioactivity of adeno-associated virus vectors. Clinical research to understand the natural history and progression of the GSDs provides invaluable outcome measures that serve as endpoints to evaluate benefits in clinical trials. While promising, gene therapy and genome editing face challenges with regard to clinical implementation, including immune responses and toxicities that have been revealed during clinical trials of gene therapy that are underway. Gene therapy for the glycogen storage diseases is under development, addressing an unmet need for specific, stable therapy for these conditions.

Dr. Koeberl, Dr. Lim, Dr. Sun, and Dr. Kishnani have developed technology that is discussed in this review. If the technology is commercially successful in the future, the developers and Duke University may benefit financially. Dr. Koeberl has served as a consultant for Sangamo Therapeutics, Moderna, Genzyme Sanofi, Amicus, and Vertex; has received grant support from Viking Therapeutics, Genzyme Sanofi, Roivant Rare Diseases, and Amicus; and has held equity in Asklepios Biopharmaceutical (AskBio), which is developing gene therapy for Pompe disease. Dr. Sun has received grant support from Valerion Therapeutics, Selecta Biosciences, Roivant Sciences, Alnylam Pharmaceuticals, Actus Therapeutics, Asklepios BioPharmaceutical, Inc. (AskBio), Codexis, Inc., APBD Research Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR079572). Dr. Kishnani has received research/grant support from Genzyme Sanofi, Amicus Therapeutics, Takeda Pharmaceutical and Kriya Therapeutics; has received consulting fees from Kriya Therapeutics, Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, Asklepios Biopharmaceutical (AskBio), Moderna, and Ultragenyx; is a member of the Pompe and Gaucher Disease Registry Advisory Board for Genzyme Sanofi, the Amicus scientific advisory board, the Baebies scientific advisory board, the Glycogen Storage Disease 1a Advisory Board for Moderna and Ultragenyx; has held equity in Asklepios BioPharmaceutical (AskBio); and has equity options from Kriya Therapeutics and Maze Therapeutics. Dr. Koch, Dr. Brooks, and Dr. Arnson report no disclosures.

• R01 AR079223/AR/NIAMS NIH HHS/United States
• R01 AR079572/AR/NIAMS NIH HHS/United States
• R01AR079223/AR/NIAMS NIH HHS/United States