Disruption of the <i>CFTR</i> Gene Produces a Model of Cystic Fibrosis in Newborn Pigs

TLDR

Although CFTR was identified nearly twenty years ago, many questions about cystic fibrosis pathogenesis remain unanswered, and the disease is still incurable; mouse models lack the full spectrum of human CF manifestations. The study aimed to generate a pig model with both CFTR alleles disrupted to better recapitulate human cystic fibrosis. The authors used targeted gene disruption to knock out both CFTR alleles in pigs, leveraging their anatomical similarity to humans. Newborn CFTR‑knockout pigs displayed defective chloride transport and developed meconium ileus, pancreatic destruction, and biliary cirrhosis, mirroring human newborn CF, and the model offers a platform to investigate pathogenesis and develop therapies.

Abstract

Almost two decades after CFTR was identified as the gene responsible for cystic fibrosis (CF), we still lack answers to many questions about the pathogenesis of the disease, and it remains incurable. Mice with a disrupted CFTR gene have greatly facilitated CF studies, but the mutant mice do not develop the characteristic manifestations of human CF, including abnormalities of the pancreas, lung, intestine, liver, and other organs. Because pigs share many anatomical and physiological features with humans, we generated pigs with a targeted disruption of both CFTR alleles. Newborn pigs lacking CFTR exhibited defective chloride transport and developed meconium ileus, exocrine pancreatic destruction, and focal biliary cirrhosis, replicating abnormalities seen in newborn humans with CF. The pig model may provide opportunities to address persistent questions about CF pathogenesis and accelerate discovery of strategies for prevention and treatment.