Using cellular models to inform diagnoses and predict therapeutic responses of individuals with cystic fibrosis

Cystic fibrosis (CF) continues to be a premier disease model for genetics research by demonstrating many of the successes of molecular genetics research as well as the challenges still facing the genetics research community. Research in CF has elucidated the mechanisms underlying specific DNA variants that cause disease, leading to the development of modulator therapies that are able to very specifically and potently improve the function of specific variant versions of CFTR protein. The eventual goal of providing effective therapy to all individuals with CF will depend on the expansion of the approval of currently available drugs to all individuals who would benefit and the development of novel compounds to treat variants that are unresponsive to current modulators. These two goals will be dependent upon detailed molecular understanding of all variants found on disease associated alleles of CFTR. To this end, we have used cellular models to accurately measure CFTR function in vitro and to test the response of missense variants to CFTR small molecule drugs. The current outlook for treating CF is very optimistic as new modulators proceed through clinical trials and extend accessibility of therapies capable of treating the underlying cause of CF to a growing number of individuals

Two rare variants that affect the same amino acid in CFTR have distinct responses to ivacaftor

This is the data set for a manuscript reporting the impact of two rare cystic fibrosis-causing CFTR variants on the channel function of CFTR and the effects of the CFTR modulator ivacaftor

Capitalizing on the heterogeneous effects of CFTR nonsense and frameshift variants to inform therapeutic strategy for cystic fibrosis.

CFTR modulators have revolutionized the treatment of individuals with cystic fibrosis (CF) by improving the function of existing protein. Unfortunately, almost half of the disease-causing variants in CFTR are predicted to introduce premature termination codons (PTC) thereby causing absence of full-length CFTR protein. We hypothesized that a subset of nonsense and frameshift variants in CFTR allow expression of truncated protein that might respond to FDA-approved CFTR modulators. To address this concept, we selected 26 PTC-generating variants from four regions of CFTR and determined their consequences on CFTR mRNA, protein and function using intron-containing minigenes expressed in 3 cell lines (HEK293, MDCK and CFBE41o-) and patient-derived conditionally reprogrammed primary nasal epithelial cells. The PTC-generating variants fell into five groups based on RNA and protein effects. Group A (reduced mRNA, immature (core glycosylated) protein, function 1% (n = 5)), Group D (reduced mRNA, mature protein, function >1% (n = 5)) and Group E (aberrant RNA splicing, mature protein, function > 1% (n = 1)) variants responded to modulators. Increasing mRNA level by inhibition of NMD led to a significant amplification of modulator effect upon a Group D variant while response of a Group A variant was unaltered. Our work shows that PTC-generating variants should not be generalized as genetic 'nulls' as some may allow generation of protein that can be targeted to achieve clinical benefit