Treating neutropenia and neutrophil dysfunction in glycogen storage disease type Ib with an SGLT2 inhibitor.

Abstract

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.

• Authors: Saskia B Wortmann, Johan L K Van Hove, Terry G J Derks, Nathalie Chevalier, Vijaya Knight, Andreas Koller, Esmee Oussoren, Johannes A Mayr, Francjan J van Spronsen, Florian B Lagler, Sommer Gaughan, Emile Van Schaftingen, Maria Veiga-da-Cunha
• Journal: Blood (Blood) Vol. 136 Issue 9 Pg. 1033-1043 (08 27 2020) ISSN: 1528-0020 [Electronic] United States
• PMID: 32294159 (Publication Type: Case Reports, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 by The American Society of Hematology.

Chemical References

• Benzhydryl Compounds
• Blood Glucose
• Glucosides
• Hexosephosphates
• LAMP2 protein, human
• Lysosomal-Associated Membrane Protein 2
• Sodium-Glucose Transporter 2 Inhibitors
• Granulocyte Colony-Stimulating Factor
• 1,5-anhydroglucitol-6-phosphate
• empagliflozin

Topics

• Benzhydryl Compounds (adverse effects, therapeutic use)
• Blood Glucose (analysis)
• Chemotaxis, Leukocyte (drug effects)
• Child, Preschool
• Drug Repositioning
• Drug Resistance
• Female
• Glucosides (adverse effects, therapeutic use)
• Glycogen Storage Disease Type I (blood, complications, immunology)
• Granulocyte Colony-Stimulating Factor (therapeutic use)
• Granulocytes (chemistry)
• Hexosephosphates (blood)
• Humans
• Infant, Newborn
• Lysosomal-Associated Membrane Protein 2 (blood)
• Male
• Neutropenia (blood, drug therapy)
• Neutrophils (pathology)
• Off-Label Use
• Respiratory Burst (drug effects)
• Sodium-Glucose Transporter 2 Inhibitors (adverse effects, therapeutic use)
• Young Adult