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Small molecule CFTR modulators have dramatically improved outcomes for people with CF (pwCF) by promoting the trafficking of defective CFTR protein to the cell surface and enhancing its activity. However, a substantial proportion of pwCF harbor genotypes which remain refractory to CFTR modulators and thus lack approved disease-modifying treatments, most commonly nonsense and splicing variants that disrupt CFTR expression at the transcript or translation level. This review delineates the molecular mechanisms underlying modulator-refractory CFTR genotypes, focusing on premature termination codons, nonsense-mediated mRNA decay (NMD), and aberrant pre-mRNA splicing. We examine how these biological phenomena determine and constrain modulator efficacy while simultaneously defining therapeutic entry points. We evaluate emerging DNA-targeted strategies, such as gene replacement and gene editing, alongside RNA-directed approaches, including mRNA replacement, antisense oligonucleotides, CFTR amplifiers, translational readthrough agents and NMD inhibition. Variant-specific sensitivity, reported clinical and preclinical evidence, and practical considerations for implementation are critically assessed. By aligning molecular defect with therapeutic modality, this framework enables rational prioritization of intervention strategies for modulator-refractory CFTR genotypes.<\/jats:p>","DOI":"10.1093\/hmg\/ddag058","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T11:19:43Z","timestamp":1781695183000},"source":"Crossref","is-referenced-by-count":0,"title":["Nucleic acid-based therapeutic strategies for modulator-refractory cystic fibrosis-causing variants"],"prefix":"10.1093","volume":"35","author":[{"given":"Mark D","family":"Leahy","sequence":"first","affiliation":[{"name":"BioISI-Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisboa , Campo Grande, Lisboa 1749-016 ,","place":["Portugal"]},{"name":"Advanced Disease Modelling, Targeted Drug Discovery and Gene Therapy (ADVANTAGE), Department of Pharmacological and Pharmaceutical Sciences, Faculty of Medicine, KU Leuven , 3001 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Immacolata","family":"Zollo","sequence":"additional","affiliation":[{"name":"BioISI-Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisboa , Campo Grande, Lisboa 1749-016 ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luka A","family":"Clarke","sequence":"additional","affiliation":[{"name":"BioISI-Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisboa , Campo Grande, Lisboa 1749-016 ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5467-1710","authenticated-orcid":false,"given":"Carlos M","family":"Farinha","sequence":"additional","affiliation":[{"name":"BioISI-Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisboa , Campo Grande, Lisboa 1749-016 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