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Rimoldi V, Soldà G, Capalbo A, Saba E, Giannone V, Capurro V, Lentini L, Melfi R, Lazzeri M, Porcaro L, Seia M, Aureli M, Pedemonte N, Duga S, Orrenius C, Asselta R, Straniero L
J Cyst Fibros - (-) - [2025-11-15; online 2025-11-15]
Cystic Fibrosis (CF) results from CFTR gene mutations, including splicing defects such as the polymorphic TGnTm repeat, which disrupts exon-10 inclusion and contributes to CF monosymptomatic forms. While recent advances in CF treatment have led to targeted therapies for specific CFTR defects, most splicing variants remain without an effective treatment. Small molecules, like the plant cytokine kinetin, have shown promise in correcting splicing defects in other genetic diseases, offering potential for personalized CF therapies. This study evaluated the efficacy of kinetin and its analogue, RECTAS, in correcting CFTR exon-10 splicing defects caused by TGnTm repeats. Cell models and patient-derived cells were treated with both compounds to assess their ability to enhance exon-10 inclusion. The impact of these treatments on splicing correction and CFTR protein expression was analyzed using molecular and cellular assays. Both kinetin and RECTAS improved exon-10 inclusion, with RECTAS demonstrating superior efficacy, achieving up to a four-fold increase in patient-derived cells compared to kinetin. Additionally, RECTAS consistently rescued exon-10 splicing across various TG-T alleles and successfully restored CFTR protein expression, highlighting its potential as a more potent therapeutic option. These findings identify RECTAS as an effective modulator of CFTR splicing. Rather than stand-alone therapeutics, kinetin and its analogues may act as transcript amplifiers, thereby possibly enhancing the efficacy of existing CFTR modulators. This approach could broaden treatment options for splicing-related CFTR variants and other genetic disorders.
NGI Uppsala (Uppsala Genome Center) [Service]
National Genomics Infrastructure [Service]
PubMed 41242903
DOI 10.1016/j.jcf.2025.11.006
Crossref 10.1016/j.jcf.2025.11.006
pii: S1569-1993(25)02502-0