Treating neutropenia and neutrophil dysfunction in glycogen storage disease type Ib with an SGLT2 inhibitor.
Benzhydryl Compounds
/ adverse effects
Blood Glucose
/ analysis
Chemotaxis, Leukocyte
/ drug effects
Child, Preschool
Drug Repositioning
Drug Resistance
Female
Glucosides
/ adverse effects
Glycogen Storage Disease Type I
/ blood
Granulocyte Colony-Stimulating Factor
/ therapeutic use
Granulocytes
/ chemistry
Hexosephosphates
/ blood
Humans
Infant, Newborn
Lysosomal-Associated Membrane Protein 2
/ blood
Male
Neutropenia
/ blood
Neutrophils
/ pathology
Off-Label Use
Respiratory Burst
/ drug effects
Sodium-Glucose Transporter 2 Inhibitors
/ adverse effects
Young Adult
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
27 08 2020
27 08 2020
Historique:
received:
09
12
2019
accepted:
07
04
2020
pubmed:
16
4
2020
medline:
18
3
2021
entrez:
16
4
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32294159
pii: S0006-4971(20)61759-1
doi: 10.1182/blood.2019004465
pmc: PMC7530374
doi:
Substances chimiques
Benzhydryl Compounds
0
Blood Glucose
0
Glucosides
0
Hexosephosphates
0
LAMP2 protein, human
0
Lysosomal-Associated Membrane Protein 2
0
Sodium-Glucose Transporter 2 Inhibitors
0
Granulocyte Colony-Stimulating Factor
143011-72-7
1,5-anhydroglucitol-6-phosphate
17659-59-5
empagliflozin
HDC1R2M35U
Types de publication
Case Reports
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1033-1043Subventions
Organisme : Austrian Science Fund FWF
ID : I 2741
Pays : Austria
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020 by The American Society of Hematology.
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