Abstract
The combination of elexacaftor/tezacaftor/ivacaftor (ETI) is effective in people with cystic fibrosis (CF) with at least one F508del-CFTR allele; however, approximately 10% have variants without established ETI responsiveness and are ineligible for therapy. Additionally, diagnostic confirmation or exclusion of CF can be challenging in individuals with compatible symptoms, CFTR variants of unknown significance, and indeterminate sweat chloride or nasal potential difference (NPD) results. We implemented a minimally invasive method for "theratyping" in subjects with confirmed or clinically suspected CF and a CFTR variant currently ineligible for ETI therapy. We derived air-liquid interface epithelia from airway basal cells obtained via nasal brushings; we then assessed CFTR function at baseline and in response to ETI with Ussing chambers. We present six cases highlighting the value of our theratyping approach in guiding clinical decision-making. In two subjects, theratyping demonstrated substantial improvement in CFTR function and supported approval for ETI therapy, with subsequent clinical improvements in airway mechanics, weight maintenance, microbiology, and symptom burden. Conversely, theratyping identified two subjects with CF unlikely to respond to ETI, suggesting they may be candidates for future trials of new therapeutics. Finally, in two subjects with suspected CF, theratyping demonstrated normal-range CFTR function and decreased suspicion for CF. This work highlights our theratyping approach as a practical strategy for 1) predicting ETI response in people with CF and CFTR variant currently ineligible for ETI therapy and 2) aiding in the diagnostic confirmation or exclusion of CF in cases with inconclusive sweat chloride or NPD results.