Division of Pediatrics, Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht (UMCU), Utrecht University (UU), Utrecht, the Netherlands.
Regenerative Medicine Center, UMCU, UU, Utrecht, the Netherlands.
Clin Transl Gastroenterol. 2021 Nov 18;12(11):e00427. doi: 10.14309/ctg.0000000000000427.
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.
鸟苷酸环化酶 C（GCC）的功能获得性突变可导致围产期起病的持续性腹泻。我们研究了一种特定的 GCC 抑制剂 SSP2518，以评估其治疗这种疾病的潜力。
我们研究了 SSP2518 对 3 名具有不同激活 GCC 突变的患者和对照者的肠道类器官中 GCC 介导的细胞内环鸟苷酸单磷酸（cGMP）水平以及 GCC 介导的氯离子分泌的影响，同时有无热稳定肠毒素对 GCC 的刺激。
与对照类器官相比，患者衍生的类器官具有显著更高的基础 cGMP 水平，而 SSP2518 将其降低至对照类器官中的水平。此外，SSP2518 还显著降低了热稳定肠毒素刺激后患者衍生和对照类器官中的 cGMP 水平和氯离子分泌（所有比较的 P 值均<0.05）。
我们在这项研究中报告称，GCC 抑制剂 SSP2518 可使源自 GCC 功能获得性突变患者的肠道类器官中的 cGMP 水平正常化，并显著减少囊性纤维化跨膜电导调节剂依赖性氯离子分泌，这是持续性腹泻的驱动因素。
