Cystic fibrosis is one of the most commonly inherited diseases, affecting about one in every four thousand children born in the USA, and is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene produces a channel that allows the transport of chloride ions across membranes in the body, and the many mutations identified in cystic fibrosis sufferers either reduce the activity of the channel or eliminate it entirely. This defect in chloride ion transport leads to defects in several major organs including the lungs, digestive system, pancreas, and liver, though the severity of the disease and the number of organs affected varies considerably among patients. Over the past few decades the treatment of cystic fibrosis has improved dramatically; good nutrition, physiotherapy, and the availability of antibiotics to treat the damaging lung infections that are characteristic of the disease have all contributed to an increasing life expectancy among sufferers. Nevertheless the damage to lungs frequently becomes so severe that cystic fibrosis patients require lung transplants, a procedure made possible through animal research that lead to development of the heart-lung bypass machine and immunosuppressant drugs, and many cystic fibrosis patients still die early in their 20′s and 30′s.
Following the identification of the CFTR gene in 1989 scientists sought to create animal models of cystic fibrosis with which to study the disease, and since the early 1990′s more than a dozen mouse models of cystic fibrosis have been created. In some of these the CFTR gene has been “knocked out”, in other words completely removed, but in others the mutations found in human cystic fibrosis that result in a defective channel have been introduced. These mouse models show many of the defects seen in human cystic fibrosis patients and over the past few years have yielded important new information about cystic fibrosis. An example is the discovery that much of the increase in mucus in the airways and impaired ability to clear bacteria is due to a decrease in the volume of liquid on the airway surface (1), which lead to an increased interest in the use of hypertonic saline therapy to help clear the airways. Recently scientists have been attempting to cure the underlying defects in the CFTR gene through a variety of means, an effort that has been greatly aided by the availability of mouse models. New approaches evaluated in CF mice prior to human trials include gene therapy to replace the defective CFTR gene with a functioning copy, and novel drugs such as PTC124 that masks the mutation and allows the defective CFTR gene to function normally (2).
This week a paper on the journal Science reports the creation of a pig model of cystic fibrosis (4) which shows all the abnormalities that would be expected in a human cystic fibrosis patient of a similar age. The scientists observed that the intestine, pancreas and liver of the newborn pigs showed the same defects seen in many human patients and that there was no evidence of lung defects, which agreed with the fact that the human cystic fibrosis lung disease does not appear until several months or even years after birth. It will be interesting to see how long it takes for the lung defects to become apparent in the pig, and perhaps even answer the question as to whether or not the initial development of the lung disease requires bacterial infection. Such discoveries may well help to improve therapies that seek to delay onset of the lung disease or to treat it later. Of course if the pig cystic fibrosis model is as good as it appears to be it will also prove extremely valuable for the evaluation of new drugs and gene therapy approaches to treating the cause of the disease.
An important fact to note is that the cystic fibrosis pigs created in this study are a knockout model, that is a pig where no CFTR chloride ion channel is present, and therefor reproduces the most extreme form of the human disease. I’d like to see the development of models for the less severe forms of cystic fibrosis, such as the F508 deleted mutation that produces a defective but still slightly active channel and is responsible for about two-thirds of cystic fibrosis cases. Several approaches for the treatment of cystic fibrosis seek to “fix” the defective channel, and a pig model where these approaches could be studied would be very useful. This is a small quibble though, and shouldn’t take away from the fine achievement of Christopher Rogers and colleagues.
Addendum April 2010: A follow up paper in Science Translational Medicine has confirmed that within a few months of birth the cystic fibrosis pigs do develop the lung disease seen in humans with cystic fibrosis (5). Already studies of these pigs have provided strong evidence to support the theory that impaired clearence of bacteria from the lungs is a critical event in triggering the inflammation and mucus accumulation typical of cystic fibrosis. In future expect these cystic fibrosis pigs to play an important role in the evaluation of novel CF therapies.
2) Du M. et al. “PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model ” Proc Natl Acad Sci U S A. Volume 105(6) pages 2064-2069 (2008).
3) Carvalho-Oliveira I et al. “What have we learned from mouse models for cystic fibrosis?” Expert Rev Mol Diagn. Vol. 7(4), pages 407-417 (2007)
4) Rogers C.S. et al. “Disruption of the CFTR Gene Produces a Model of Cystic Fibrosis in Newborn Pigs” Science Volume 321, pages 1837-1841 (2008)
5) Stoltz D.A et al. “Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth.”Sci Transl Med. 2010 Apr 28;2(29):29ra31. DOI:10.1126/scitranslmed.3000928