Modified G6PC (glucose-6-phosphatase, catalytic subunit) nucleic acids and glucose-6-phosphatase- (G6Pase-) enzymes with increased phosphohydrolase activity are described. Also described are vectors, such as adeno-associated virus (AAV) vectors, and recombinant AAV expressing modified G6Pase-. The disclosed AAV vectors and rAAV can be used for gene therapy applications in the treatment of glycogen storage disease, particularly glycogen storage disease type Ia (GSD-Ia), and complications thereof.

Embodiments of the instant disclosure relate to novel gene editing vectors, compositions, and methods for editing a G6PC gene to treat glucose storage diseases (e.g., GSD Ia). In certain embodiments, vectors described herein comprise one or more CRISPR/Cas9 components to allow for integration of a G6PC transgene into a target gene locus in a subject in need thereof, thereby allowing for stable expression of a therapeutic protein (e.g., glucose-6-phosphatase) and reversal and/or treatment of disease symptoms in the subject.