KOSEN 한인과학기술자네트워크

Metabolic disease (Glycogen Storage disease) GSD

Molecular Genetics of Heritable Human Disorders

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 glucose-6-phosphate (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. 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 not shared by GSD-Irs. GSD-Ib and GSD-Irs patients manifest a common myeloid phenotype of neutropenia and myeloid dysfunction not shared by GSD-Ia. Inactivation of G6PT or G6Pase-β in neutrophils leads to enhanced apoptosis that underlies neutropenia in GSD-Ib and GSD-Irs.  A deficiency in either G6PT or G6Pase-β in neutrophils prevents recycling of glucose from the ER to the cytoplasm, leading to impaired energy homeostasis that underlies neutrophil dysfunction in GSD-Ib and GSD-Irs. There is no cure for GSD-Ia, GSD-Ib, and GSD-Irs.  Animal models of the three disorders are available and are being exploited to both delineate the disease more precisely and develop new treatment approaches, including gene therapy. We have recently generated several efficacious G6Pase-α-expressing recombinant adeno-associated virus (rAAV) vectors and provided a proof of principle gene therapy in murine GSD-Ia that is safe, efficacious, and appropriate for entering clinical trials. The rAAV vector expressing a codon-optimized G6Pase-α developed in this laboratory (US patent number: 9,644,216; European patent number: EP3074510) was selected for 2018 phase I/II clinical trial for human GSD-Ia (ClinicalTrials.gov Identifier: NCT03517085).