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.