Cystic Fibrosis (CF) is the most common lethal genetic disease in Caucasians and is caused by mutations in the gene encoding a cAMP-regulated chloride channel, the cystic fibrosis transmembrane conductance regulator (CFTR). Disease manifestations include poor growth, chronic lung infection, exocrine pancreatic insufficiency, intestinal obstruction, malabsorption and reduced fertility. While recent FDA approved CFTR modulators, that restore CFTR function from endogenous mutant CFTR, have shown great promise for ameliorating aspects of the disease in children and adults with CF, some of these disease manifestations originate prenatally. These aspects of the disease could possibly be prevented if such modulators are administered in utero. In utero restoration of CFTR function is an understudied area of CF research and not surprisingly, CFTR modulators are not currently approved for prenatal use. Several medical advancements in CFTR mutation carrier testing, non-invasive prenatal testing, DNA sequencing and the existence of successful CFTR modulators have made treating CF prenatally a real possibility in the near future. However, it is not clear when prenatal CFTR restoration is necessary to prevent or reduce CF disease manifestations and even if existing CFTR modulators can be utilized in utero. To date, there have been no in vivo model systems available to the CF community to test CFTR correction strategies in utero. To overcome this limitation, we recently created two mouse models. One model allows for the restoration of CFTR function at specific developmental time points in utero and the other model allows for human CFTR mutation specific therapies to be tested in utero. These mouse models will allow us to understand how Cftr correction during development may aid in amelioration or even prevention of CF manifestations as well as test which therapies will be successful. This innovative approach to examining CFTR correction and prevention of CF disease manifestation using highly tractable model systems will lead to a better understanding of CF and its future treatment. This application?s long-term objective is to provide necessary information regarding CFTR correction so that expectations can be correctly set for future CF treatments.
The specific aims of this application are 1) To determine optimal timing of CFTR correction in utero and 2) To assess the effects of in utero correction of human F508del mutation using existing CFTR modulators. Insights from this project will lead to better treatment and improved healthcare for the 30,000 CF patients in the U.S. as well as the 70,000 CF patients worldwide.
This project utilizes novel Cystic Fibrosis (CF) mouse models to increase our understanding of the molecular and physiological consequences of loss of the cystic fibrosis transmembrane conductance regulator (CFTR) and whether or not the consequences can be corrected in utero. These models will allow for a better treatment of CF, the most common lethal genetic disease in the Caucasian population affecting 30,000 individuals in the US.
