PROJECT SUMMARY
Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding CF transmembrane
conductance regulator (CFTR), an ion channel essential for mucus hydration. Improper hydration of mucus leads
to airway inflammation, chronic pulmonary infections and abnormal mucociliary function. The major contributor
to morbidity and mortality in CF is a progressive decline in lung function. Recent advances in therapies that
modulate mutant CFTR for those with the most common CFTR mutations have led to dramatic improvements in
lung function. Despite the considerable improvements afforded by these CFTR modulators, there is no evidence
that they improve underlying airway inflammation as lung function continues to decline over time. The
identification of therapies that target this inflammation will be critical to ensuring that the long-term benefits of
CFTR modulators are fully realized. Preliminary in vitro evidence from the applicant demonstrates that losartan,
a common anti-hypertensive medication with known anti-inflammatory properties, can improve the efficacy of
CFTR modulators in the presence of inflammation. This proposal aims to further our understanding of the impact
of inflammation on response to CFTR modulator therapy and, using a novel enrollment strategy, evaluate if
losartan is able to further improve CFTR function in those with CF on the modulator
elexacaftor/tezacaftor/ivacaftor (ETI). In aim 1, we will sample the nasal fluid of those with CF on ETI and, using
regression analysis, examine the association of expression levels of the inflammatory marker TGF-¿1 on change
in lung function after starting ETI. In aim 2a, we will conduct a randomized, double-blind clinical trial of losartan
to improve CFTR function, as measured by sweat chloride, in those with CF on ETI. We will utilize a prognostic
enrichment strategy by including only those with the persistently elevated sweat chloride levels after starting ETI.
Additionally, in aim 2b, we will correlate the response in aim 2a with in vitro measurement of CFTR current in
patient-derived nasal epithelial cells (NECs) treated with losartan and ETI in order to understand if it could be
utilized as a prediction of in vivo response. The long-term goal of the applicant is to become an independent
investigator who, through application of novel, adaptive, clinical trial techniques, evaluates therapies which have
the potential to improve outcomes of those with CF. He has prior experience in using in vitro and in vivo methods
to further understanding of the effects of inflammation and hyperglycemia on mucociliary clearance and formal
training in basic biostatistics and clinical research. The career development plan associated with this proposal
pairs an experienced, diverse mentoring team with additional training in advanced biostatistics, adaptive clinical
trial design and utilization of patient-derived NECs. This will uniquely position the applicant to design and lead
clinical trials using efficient, adaptive strategies to test the next generation of therapies for those with CF.