Treating neutropenia and neutrophil dysfunction in glycogen storage disease IB with an SGLT2-inhibitor.

Neutropenia and neutrophil dysfunction cause serious infections and inflammatory bowel disease in glycogen storage disease Ib (GSD-Ib). Our discovery that accumulating 1,5-anhydroglucitol-6-phosphate causes neutropenia in a G6PC3-deficient mouse model and in the two rare diseases (GSD-Ib and G6PC3-deficiency) led us to repurpose the widely used antidiabetic drug empagliflozin, an inhibitor of the renal glucose co-transporter SGLT2. Off-label use of empagliflozin in four GSD-Ib patients with incomplete response to granulocyte colony stimulating factor (GCSF) treatment decreased serum 1,5-anhydroglucitol and neutrophil 1,5-anhydroglucitol-6-phosphate levels within one month. Clinically, symptoms of frequent infections, mucosal lesions, and inflammatory bowel disease resolved, and no symptomatic hypoglycemia was observed. GCSF could be discontinued in two patients and tapered down - by 57 and 81%, respectively - in the other two. The fluctuating neutrophil numbers in all patients were increased and stabilized. We further show the improved neutrophil function: we show a normal oxidative burst (in three of three patients tested, 3/3), a corrected protein glycosylation (2/2), as well as a normal neutrophil chemotaxis (1/1), and bactericidal activity (1/1) under treatment. In conclusion, the glucose lowering drug empagliflozin, used for the frequent and acquired disease type 2 diabetes, was successfully repurposed for treating neutropenia and neutrophil dysfunction in the rare inherited metabolic disorder GSD-Ib without causing symptomatic hypoglycemia. We ascribe this to an improvement of the neutrophil function due to the reduction of the intracellular concentration of 1,5-anhydroglucitol-6-phosphate