Friday, May 9, 2025
5/9/2025
Pulmonary and pancreatic response to cystic fibrosis modulator therapy in young children - Project summary Highly effective modulator therapy (HEMT) which dramatically improves pulmonary function has been developed for people with cystic fibrosis (CF). In 2019, the HEMT elexacaftor, tezacaftor, ivacaftor (ETI) became available for the 90% of CF teens and adults with at least one F508del mutation. Use of ETI is now widespread in the US and is standard of care. With chronic use of ETI, some people with CF (PwCF) have resolution of pulmonary symptoms and successfully wean burdensome daily pulmonary treatments. Unfortunately, the pulmonary response is variable and there are some PwCF who have no, or only mild, pulmonary improvement with ETI. Furthermore, there is no evidence of improvement in either exocrine or endocrine pancreatic function in CF teens and adults with ETI. This lack of a pancreatic response most likely is related to the fact that in CF the pancreas is largely replaced by lipofibrotic tissue by the teenage years, leaving little to no pancreatic tissue for ETI- mediated restoration of function. However, recent data show that younger CF children may have a significant pancreatic response to ETI. In April 2023, the FDA approved ETI for CF children aged 2 to 5 years. Our overall hypothesis is that in this young age group, chronic ETI will prevent progression of airway disease to bronchiectasis, prevent further destruction of pancreatic exocrine tissue, possibly permit repair/regeneration of exocrine function, and prevent CF related diabetes (CFRD), the most serious complication of pancreatic disease. In this project, we propose to study a cohort of 30 CF children aged 2- to 5-years old before and four years after starting ETI for clinical indications. We aim to: 1. Determine the impact of ETI-mediated CFTR restoration on progression of airway disease in these young CF children; 2. Determine the impact of ETI-mediated CFTR restoration on pancreatic exocrine and endocrine function in this cohort; and 3. Elucidate computational phenotypes of therapeutic responsiveness in the lungs and the pancreas and their trajectories using machine learning. This project is important as it has the potential to usher in the next generation of therapeutics for CF which will be the initiation of HEMT in infancy to prevent the many later manifestations of CF including bronchiectasis, pancreatic exocrine insufficiency, and CFRD.
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