A Potential Treatment of Congenital Sodium Diarrhea in Patients With Activating GUCY2C Mutations

Gain-of-function mutations in guanylyl cyclase C (GCC) result in persistent diarrhea with perinatal onset. We investigated a specific GCC inhibitor, SSP2518, for its potential to treat this disorder. We investigated the effect of SSP2518 on GCC-mediated intracellular cyclic guanosine monophosphate (...

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Bibliographic Details
Published in:Clinical and translational gastroenterology 2021-11, Vol.12 (11), p.e00427-e00427
Main Authors: van Vugt, Anke H M, Bijvelds, Marcel J C, de Jonge, Hugo R, Meijsen, Kelly F, Restin, Tanja, Bryant, Manuel B, Ballauff, Antje, Koot, Bart, Müller, Thomas, Houwen, Roderick H J, Janecke, Andreas R, Middendorp, Sabine
Format: Article
Language:English
Subjects:
Abnormalities, Multiple - drug therapy
Abnormalities, Multiple - genetics
Abnormalities, Multiple - metabolism
Brief Report
Chloride
Congenital diseases
Cyclic GMP - metabolism
Cystic fibrosis
Diarrhea
Diarrhea - congenital
Diarrhea - drug therapy
Diarrhea - genetics
Diarrhea - metabolism
E coli
Functional GI Disorders
Gain of Function Mutation
Heterocyclic Compounds, 4 or More Rings - therapeutic use
Humans
Kinases
Ligands
Metabolism, Inborn Errors - drug therapy
Metabolism, Inborn Errors - genetics
Metabolism, Inborn Errors - metabolism
Mutation
Patients
Receptors, Enterotoxin - antagonists & inhibitors
Receptors, Enterotoxin - genetics
Small intestine
Sodium
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Summary:Gain-of-function mutations in guanylyl cyclase C (GCC) result in persistent diarrhea with perinatal onset. We investigated a specific GCC inhibitor, SSP2518, for its potential to treat this disorder. We investigated the effect of SSP2518 on GCC-mediated intracellular cyclic guanosine monophosphate (cGMP) levels and on GCC-mediated chloride secretion in intestinal organoids from 3 patients with distinct activating GCC mutations and from controls, with and without stimulation of GCC with heat-stable enterotoxin. Patient-derived organoids had significantly higher basal cGMP levels than control organoids, which were lowered by SSP2518 to levels found in control organoids. In addition, SSP2518 significantly reduced cGMP levels and chloride secretion in patient-derived and control organoids (P < 0.05 for all comparisons) after heat-stable enterotoxin stimulation. We reported in this study that the GCC inhibitor SSP2518 normalizes cGMP levels in intestinal organoids derived from patients with GCC gain-of-function mutations and markedly reduces cystic fibrosis transmembrane conductance regulator-dependent chloride secretion, the driver of persistent diarrhea.
ISSN:2155-384X
2155-384X
DOI:10.14309/ctg.0000000000000427