In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis

Abstract

In utero and early postnatal functional rescue of cystic fibrosis transmembrane conductance regulator improves survival in cystic fibrosis ferrets. Tackling cystic fibrosis in the womb Cystic fibrosis (CF) is a multiorgan disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Abnormalities are observed early during development. Sun et al. reasoned that early intervention using the approved drug VX-770 (ivacaftor), a CFTR modulator, could prevent the development of such abnormalities. The authors tested the effect of in utero and early postnatal VX-770 administration in a ferret model of CF. Lung, gastrointestinal, pancreatic, and male reproductive pathologies were partially prevented in ferrets treated prior to and following birth. The results suggest that CFTR plays a critical role in early organ development and that prenatal and postnatal treatment might prevent developmental pathologies and onset of disease. Cystic fibrosis (CF) is a multiorgan disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). In patients with CF, abnormalities initiate in several organs before birth. However, the long-term impact of these in utero pathologies on disease pathophysiology is unclear. To address this issue, we generated ferrets harboring a VX-770 (ivacaftor)–responsive CFTRG551D mutation. In utero VX-770 administration provided partial protection from developmental pathologies in the pancreas, intestine, and male reproductive tract. Homozygous CFTRG551D/G551D animals showed the greatest VX-770–mediated protection from these pathologies. Sustained postnatal VX-770 administration led to improved pancreatic exocrine function, glucose tolerance, growth and survival, and to reduced mucus accumulation and bacterial infections in the lung. VX-770 withdrawal at any age reestablished disease, with the most rapid onset of morbidity occurring when withdrawal was initiated during the first 2 weeks after birth. The results suggest that CFTR is important for establishing organ function early in life. Moreover, this ferret model provides proof of concept for in utero pharmacologic correction of genetic disease and offers opportunities for understanding CF pathogenesis and improving treatment.