SLGT2 Inhibitor Rescues Myelopoiesis in G6PC3 Deficiency

Abstract The energy metabolism of myeloid cells depends primarily on glycolysis. 1,5-anhydroglucitol (1,5AG), a natural monosaccharide is erroneously phosphorylated by glucose-phosphorylating enzymes to produce 1,5-anhydroglucitol-6-phosphate (1,5AG6P), a powerful inhibitor of hexokinases. The endoplasmic reticulum transporter (SLC37A4/G6PT) and the phosphatase G6PC3 co-operate to dephosphorylate 1,5AG6P. Failure to eliminate 1,5AG6P is the mechanism of neutrophil dysfunction and death in G6PC3-deficient mice. SLGT2-inhibitor reduces 1,5AG level in the blood and restores the neutrophil count in G6PC3-deficient mice. In the investigator-initiated study, a 30 year-old G6PC3-deficient woman with recurrent infections, distressing gastrointestinal symptoms and multi-lineage cytopenia was treated with an SLGT2-inhibitor. A significant increase in all the hematopoietic cell lineages and substantial improvement in the quality of life was observed.