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

Author:

Wortmann Saskia B.123ORCID,Van Hove Johan L. K.45,Derks Terry G. J.6ORCID,Chevalier Nathalie7,Knight Vijaya8,Koller Andreas9ORCID,Oussoren Esmee10,Mayr Johannes A.1ORCID,van Spronsen Francjan J.6ORCID,Lagler Florian B.111ORCID,Gaughan Sommer4,Van Schaftingen Emile712ORCID,Veiga-da-Cunha Maria712ORCID

Affiliation:

1. University Children’s Hospital, Paracelsus Medical University (PMU), Salzburg, Austria;

2. Institute of Human Genetics, Technical University München, Munich, Germany;

3. Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, The Netherlands;

4. Section of Clinical Genetics and Metabolism, Department of Pediatrics, School of Medicine, University of Colorado, Aurora, CO;

5. Department of Genetics, Children’s Hospital Colorado, Aurora, CO;

6. Section of Metabolic Diseases, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;

7. Groupe de Recherches Metaboliques, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium;

8. Section of Allergy and Immunology, Department of Pediatrics, School of Medicine, University of Colorado, Denver, CO;

9. Research Program for Experimental Ophthalmology, Department of Ophthalmology and Optometry, University Hospital, PMU, Salzburg, Austria;

10. Department of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands;

11. Institute for Inherited Metabolic Disease, PMU, Salzburg, Austria; and

12. Walloon Excellence in Lifesciences and Biotechnology, Brussels, Belgium

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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