We conduct research to delineate the pathophysiology and develop novel therapies for the three subtypes of type I glycogen storage disease (GSD-I), GSD-Ia, GSD-Ib, and GSD-Irs (GSD-I related syndrome). GSD-Ia is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC), GSD-Ib is caused by a deficiency in the G6P transporter (G6PT or SLC37A4), and GSD-Irs, also known as severe congenital neutropenia syndrome type 4 is caused by a deficiency in G6Pase-β. G6Pase-α and G6Pase-β are endoplasmic reticulum (ER)-bound G6P hydrolases, with active sites lying inside the lumen, which depend upon G6PT to translocate G6P from the cytoplasm into the ER lumen. We show that G6PT and G6Pase-α (or G6Pase-β) are functionally co-dependent. We further show that the G6PT/G6Pase-α complex maintains interprandial glucose homeostasis while the G6PT/G6Pase-β complex maintains energy homeostasis and functionality of neutrophils. GSD-Ia and GSD-Ib patients manifest a common metabolic phenotype of impaired glucose homeostasis and long-term complications of hepatocellular adenoma/carcinoma (HCA/HCC) and renal disease. GSD-Ib and GSD-Irs patients manifest a common myeloid phenotype of neutropenia and myeloid dysfunction. More recently, we elucidated the mechanisms underlying HCA/HCC development in mouse GSD-Ia and the mechanism underlying the low incidence of HCA in GSD-Ia mice receiving gene therapy. There is no cure for GSD-Ia, GSD-Ib, and GSD-Irs. We have developed mouse models of these disorders which are being exploited to both delineate the disease more precisely and develop new treatment approaches, including gene therapy.
To translate our findings into clinical benefits for GSD-I patients, we generated efficacious rAAV vectors and undertaken extensive preclinical characterization of GSD-I gene therapy. Our rAAV-mediated gene therapy in animal models of GSD-I has provided proof of principle studies that establish gene therapy for GSD-Ia and GSD-Ib to be safe and efficacious. In 2018, our rAAV-G6PC vector technology (US patent # 9,644,216) was licensed to Ultragenyx Pharmaceutical Inc who are currently undertaking a phase I/II clinical trial for GSD-Ia (NCT03517085). We have continued improving our vector technology and generated a novel rAAV-G6PC-S298C vector (US patent #10,415,044) with increased efficacy and devoid of potential problems associated with codon-optimization that may reduce efficacy. To explore alternative genetic technologies for GSD-I therapies, we generated a G6pc-R83C mouse line harboring the pathogenic human G6PC-p.R83C mutation and shown that the G6pc-R83C mice manifest a phenotype mimicking human GSD-Ia. Using these mice, we then showed that the CRISPR-Case9-based gene editing, when administered to newborn mice can effectively correct the G6PC mutation in the liver and normalize metabolic abnormalities in the G6pc-R83C mice. Our study provides a proof of concept for CRISPR-based correction of a pathogenic G6PC variant in a mouse model.