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

Wortmann, S. B., Van Hove, J. L. K., Derks, T. G. J., Chevalier, N., Knight, V., Koller, A., Oussuren, E., Mayr, J. A., van Spronsen, F. J., Lagler, F. B., Gaughan, S., Van Schaftingen, E. & Veiga-da-Cunha, M., 15-Apr-2020, In : Blood. 136, 9, p. 1033-1043 27 p.

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

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DOI

  • Saskia B Wortmann
  • Johan L K Van Hove
  • Terry G J Derks
  • Nathalie Chevalier
  • Vijaya Knight
  • Andreas Koller
  • Esmee Oussuren
  • Johannes Am Mayr
  • Francjan J van Spronsen
  • Florian B Lagler
  • Sommer Gaughan
  • Emile Van Schaftingen
  • Maria Veiga-da-Cunha

Neutropenia and neutrophil dysfunction cause serious infections and inflammatory bowel disease in glycogen storage disease type Ib (GSD-Ib). Our discovery that accumulating 1,5-anhydroglucitol-6-phosphate (1,5AG6P) caused neutropenia in a glucose-6-phosphatase 3 (G6PC3)-deficient mouse model and in 2 rare diseases (GSD-Ib and G6PC3 deficiency) led us to repurpose the widely used antidiabetic drug empagliflozin, an inhibitor of the renal glucose cotransporter sodium glucose cotransporter 2 (SGLT2). Off-label use of empagliflozin in 4 GSD-Ib patients with incomplete response to granulocyte colony-stimulating factor (GCSF) treatment decreased serum 1,5AG and neutrophil 1,5AG6P levels within 1 month. Clinically, symptoms of frequent infections, mucosal lesions, and inflammatory bowel disease resolved, and no symptomatic hypoglycemia was observed. GCSF could be discontinued in 2 patients and tapered by 57% and 81%, respectively, in the other 2. The fluctuating neutrophil numbers in all patients were increased and stabilized. We further demonstrated improved neutrophil function: normal oxidative burst (in 3 of 3 patients tested), corrected protein glycosylation (2 of 2), and normal neutrophil chemotaxis (1 of 1), and bactericidal activity (1 of 1) under treatment. In summary, the glucose-lowering SGLT2 inhibitor empagliflozin, used for 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 in neutrophil function resulting from the reduction of the intracellular concentration of 1,5AG6P.

Original languageEnglish
Pages (from-to)1033-1043
Number of pages27
JournalBlood
Volume136
Issue number9
Publication statusE-pub ahead of print - 15-Apr-2020

ID: 123236501