{"doi":"10.17615/pgag-s631","title":"Restoration of R117H CFTR folding and function in human airway cells through combination treatment with VX-809 and VX-770","abstract":"Cystic fibrosis (CF) is a lethal recessive genetic disease caused primarily by the F508del mutation in the CF transmembrane conductance regulator (CFTR). The potentiator VX-770 was the first CFTR modulator approved by the FDA for treatment of CF patients with the gating mutation G551D. Orkambi is a drug containing VX-770 and corrector VX809 and is approved for treatment of CF patients homozygous for F508del, which has folding and gating defects. At least 30% of CF patients are heterozygous for the F508del mutation with the other allele encoding for one of many different rare CFTR mutations. Treatment of heterozygous F508del patients with VX-809 and VX-770 has had limited success, so it is important to identify heterozygous patients that respond to CFTR modulator therapy. R117H is a more prevalent rare mutation found in over 2,000 CF patients. In this study we investigated the effectiveness of VX-809/VX-770 therapy on restoring CFTR function in human bronchial epithelial (HBE) cells from R117H/F508del CF patients. We found that VX-809 stimulated more CFTR activity in R117H/F508del HBEs than in F508del/F508del HBEs. R117H expressed exclusively in immortalized HBEs exhibited a folding defect, was retained in the ER, and degraded prematurely. VX-809 corrected the R117H folding defect and restored channel function. Because R117 is involved in ion conductance, VX-770 acted additively with VX-809 to restore CFTR function in chronically treated R117H/F508del cells. Although treatment of R117H patients with VX-770 has been approved, our studies indicate that Orkambi may be more beneficial for rescue of CFTR function in these patients.","journal":"UNC Libraries","year":2020,"id":136367,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9577,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":402969,"name":"Deborah M. Cholon","orcid":"0000-0002-9396-0005","position":1,"is_corresponding":false},{"id":576191,"name":"Jhuma Das","orcid":"0000-0003-3548-3105","position":2,"is_corresponding":false},{"id":578776,"name":"Pattarawut Sopha","orcid":"0000-0001-8092-5828","position":3,"is_corresponding":false},{"id":149320,"name":"Nikolay V. Dokholyan","orcid":"0000-0002-8225-4025","position":4,"is_corresponding":false},{"id":595443,"name":"Imron G. Chaudhry","orcid":null,"position":5,"is_corresponding":false},{"id":425648,"name":"Douglas Cyr","orcid":"0000-0002-4928-3414","position":6,"is_corresponding":false},{"id":402971,"name":"Martina Gentzsch","orcid":"0000-0002-9435-0321","position":7,"is_corresponding":false},{"id":72632,"name":"Scott H. Randell","orcid":"0000-0001-5351-2841","position":8,"is_corresponding":false},{"id":549445,"name":"Scott A. Houck","orcid":null,"position":9,"is_corresponding":false},{"id":402970,"name":"Nancy L. Quinney","orcid":"0000-0003-3437-9621","position":10,"is_corresponding":false},{"id":578777,"name":"Hong Yu Ren","orcid":"0000-0002-8402-0468","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:16:48.793683Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}