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. 2021 Nov 18;12(11):e00427.
doi: 10.14309/ctg.0000000000000427.

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

Anke H M van Vugt  1   2 , Marcel J C Bijvelds  3 , Hugo R de Jonge  3 , Kelly F Meijsen  3 , Tanja Restin  4   5 , Manuel B Bryant  4 , Antje Ballauff  6 , Bart Koot  7 , Thomas Müller  8 , Roderick H J Houwen  1 , Andreas R Janecke  8   9 , Sabine Middendorp  1   2   10
Affiliations

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

Anke H M van Vugt et al. Clin Transl Gastroenterol. .

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Discussion: 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.

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Conflict of interest statement

Guarantor of the article: Roderick H.J. Houwen, MD, PhD and Andreas R. Janecke, MD

Specific author contributions: H.R.d.J., R.H.J.H., A.R.J., and S.M.: conceptualization. A.H.M.v.V., M.J.C.B., and S.M.: organoid generation, processing, cGMP determination, and qRT-PCR. K.F.M.: transmembrane chloride measurements. T.R., M.B.B., A.B., B.K., and T.M.: involved in patient care and access to samples. All authors contributed to the revision of the manuscript.

Financial support: This work was supported by Grant NWO-ZonMW-VIDI 016.146.353 to S.M.

Potential competing interests: None to report.

Figures

Figure 1.
Figure 1.
Elevated basal and stimulated cGMP levels in patient-derived organoids are reversed by SSP2518. cGMP levels in patient-derived and control organoid monolayers, in the absence or presence of GCC inhibitor SSP2518, without (a) or after (b) apical ST stimulation (mean ± SE; number of technical replicates as indicated within/above bars). cGMP, cyclic guanosine monophosphate; GCC, guanylyl cyclase C; ns, no statistically significant difference; ST, heat stable enterotoxin.
Figure 2.
Figure 2.
ST-dependent GCC-mediated chloride secretion across CSD organoid monolayers: (a) in ileum (control 1 and P1) decreases on SSP2518 treatment; (b) in ileum (P1 and control 1) or duodenum (P2, P3). Mean ± SE of 3 technical replicates. CSD, congenital sodium diarrhea; GCC, guanylyl cyclase C; ST, heat stable enterotoxin.
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References

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