Guanylate cyclase 2C agonism corrects CFTR mutants

Area of Science:

• Gastroenterology
• Genetics
• Molecular Biology

Background:

• Cystic fibrosis (CF) is a genetic disorder impacting fluid secretion in multiple organs, including the intestine.
• While lung and pancreatic issues are common, constipation is an underreported CF complication affecting nearly half of patients.
• Increasing lifespans in CF necessitate better management of gastrointestinal manifestations like constipation.

Purpose of the Study:

• To investigate the potential of guanylate cyclase 2C (GCC) as a therapeutic target for CF-associated intestinal dysfunction.
• To explore GCC's role in ameliorating intestinal fluid deficits in CF.

Main Methods:

• Utilized CF patient-derived intestinal organoids (spheres) with common CFTR mutations (F508del/F508del and R117H/R117H).
• Administered GCC agonists to assess functional rescue of CFTR.
• Examined the effect of GCC coexpression and activation on F508del CFTR processing and endoplasmic reticulum (ER) exit.

Main Results:

• GCC agonism successfully rescued CFTR function in CF patient-derived intestinal spheres.
• GCC activation facilitated the proper processing and ER exit of the F508del CFTR mutant.
• This suggests GCC acts as a biological corrector for CFTR, similar to existing therapies like VX-809.

Conclusions:

• Guanylate cyclase 2C (GCC) demonstrates a novel role as a biological corrector and potentiator of CFTR in the intestine.
• Targeting GCC offers a promising therapeutic strategy to address intestinal fluid deficits and constipation in cystic fibrosis patients.