Paediatric disorders
How useful are cystic fibrosis mouse models?

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Cystic fibrosis is a multi-system lethal genetic disorder. Mutations in the gene that encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) are the basis of this disorder. Currently, a variety of CF mouse models have been developed for in-depth studies. They provide significant insight into the pathophysiology; however, these models do not always mimic the human disease. In this review we will summarize the available models and highlight the characteristics that have made them important tools for advancing our understanding of CF pathophysiology and for drug development.

Section editor:

Gabriel Haddad – Pediatrics Department, University of California, San Diego, CA, USA

Introduction

Cystic fibrosis is one of the most common multi-system life shortening genetic disorders in the Caucasian population affecting one in 2500–3500 live births. The disease affects the respiratory tract, digestive tract, eccrine sweat glands and reproductive tracts [1]. CF is a life shortening with an average life expectancy of 35 years. The genetic basis for the disease was identified in 1989 when the gene that encodes for the cystic fibrosis transmembrane conductance regulator [CFTR] was identified by Collins, Riordan and Tsui [2]. Soon after the identification of the gene research began to develop animal models that would help elucidate the natural history of the basic pathophysiology of this deadly disease. Investigators also hoped that these models would provide a viable model for drug development and gene therapy development. Presently a variety of mouse models are available and they have provided significant insight into many aspects of the disease process; however, the mouse models do not always mimic the human disease. For instance the mice do not develop spontaneous Pseudomonas bronchitis and suppurative lung disease that is a hallmark of the human disease process. This has led some investigators to abandon these models. In this review we will summarize the available models and highlight the characteristics that have made them important tools for advancing our understanding of the pathophysiology that leads to end organ damage and as in vivo models for drug development.

Section snippets

Murine models of CF

Murine models of CF were developed shortly after the identification of the CFTR gene. The first models were generated by using a gene targeting strategy in which the endogenous CFTR gene is disrupted in embryonic stem cells. This strategy results in a null allele and no detectable mRNA nor functional protein and was used to generate several models (Table 1). Alternatively, several groups used an insertional method to disrupt the endogenous CFTR gene. These models produce low levels of CFTR mRNA

The clinical phenotypes of CF mouse models

The clinical manifestations of cystic fibrosis are diverse and span many organ systems. Common respiratory manifestations include nasal polyps, sinus disease, chronic obstructive lung disease which results in respiratory failure [7]. The gastrointestinal manifestations include focal biliary cirrhosis, distal ileal obstruction, exocrine pancreatic insufficiency, meconium ileus and rectal prolapse. Women demonstrate decreased fertility and the majority of males are infertile owing to bilateral

Summary

The murine models display many manifestations observed in the human disease including alterations in respiratory and intestinal epithelial electrophysiology, robust airway inflammation, intestinal obstruction, pancreatic dysfunction, hepatobiliary disease and bone disease. However, many of these manifestations are much milder in the CF mouse when compared with humans. Moreover, the spontaneous chronic pseudomonas bronchitis that is a hallmark finding in humans is not observed in any of the

Usefulness of the models and future directions

Because there are species differences in the respiratory tract between mice and humans the models might allow us to determine how these differences impact the disease state. For instance unlike humans, the mouse does not have submucosal glands in the lower respiratory tract and it has an alternative chloride channel in the lower tract. Both of these differences might provide the mouse with protection from chronic colonization with the common bacteria usually observed in CF airways.

In addition,

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