Correction of Nonsense Mutations in Cystic Fibrosis

Optimization of Correcting Molecules of Nonsense Mutations in Epithelial Cells of the Upper Airways of Patients With Cystic Fibrosis With Nonsense Mutations in the CFTR Gene

Status

Recruiting

Phases

Unknown

Study type

Observational

Source

ClinicalTrials.gov

Registry ID

NCT03670472

Enrollment

Registered

2018-09-13

Start date

2016-02-03

Completion date

2030-01-01

Last updated

2026-05-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cystic Fibrosis

Keywords

Cystic fibrosis, nonsense mutations, CFTR gene, nasal epithelial cells, nonsense mutation readthrough

Brief summary

The presence of a nonsense mutation leads to the rapid degradation of the carrier mRNA mutation by a mechanism called NMD (nonsense-mediated mRNA decay) \[6, 13\]. There are currently 3 main strategies at least for correcting nonsense mutations: exon skipping, inhibition of NMD and nonsense mutation readthrough. In the laboratory, we developed a strategy for correcting nonsense mutations combining inhibition of NMD and activation of translecture. For this purpose, we have constructed screening systems to identify NMD-inhibiting and/or readthrough enhancers. The molecules thus identified are then tested on cell lines and in murine models carrying a nonsense mutation. One of our goals is to select a set of molecules that can correct effectively nonsense mutations. For this we have to test these molecules on a great diversity of nonsense mutations. This work will: * determine if we can correct all the nonsense mutations tested with at least one of our molecules * determine what is common within a group of mutations corrected by a given molecule * be able to assign the parameters that make one mutation is corrected by one molecule and not or little by another. This study will therefore improve our theoretical knowledge on the recognition of premature stop codons but also to propose therapeutic approaches for the correction of nonsense mutations of the CFTR gene in cystic fibrosis in a targeted way for a patient.

Interventions

OTHERsmear of nasal fossae

1 smear of nasal fossae during a usual or scheduled visit

Study design

Observational model

CASE_CONTROL

Time perspective

PROSPECTIVE

Eligibility

Sex/Gender

ALL

Age

8 Years to No maximum

Healthy volunteers

Inclusion criteria

* Male / female adults and minors aged 8 years and over * Patients with cystic fibrosis and carry a nonsense mutation on the 2 alleles of the gene coding for the CFTR channel. * Patients whose genotype of patients concerning the CFTR gene is known. * Patients with social security * Major patients who have given their consent * Minor patients with parental authorization

Exclusion criteria

* Patients who have a mutation other than nonsense in the CFTR gene * Patients whose CFTR gene was not sequenced on the 2 alleles * Patients not wishing to participate in this study or persons not giving or not able to give consent. * Pregnant or lactating women * Patients under curatorship or guardianship

Design outcomes

Primary

Measure	Time frame	Description
Transport of iodide ions through the CEVAS membrane	less than 48hrs after the collect.	Patient cells with be cultured in BEGM (Lonza) medium and incubated with corrector of nonsense mutations for 20 hours and with a fluorescent molecule called SPQ (for 6-methoxy-N-3'-sulfopropylquinolinium). Iodine can bind SPQ and will quench the SPQ fluorescence. Nitrates bind SPQ without quenching SPQ fluorescence. By placing patient cells first into an iodine-rich medium to quench the SPQ fluorescence and second into a nitrate-rich medium, we will be able to measure the level of functional CFTR protein present in these cells by measuring the re-apparition of fluorescence using fluorimeter. Indeed, nitrate will be able to replace iodine on SPQ without quenching SPQ fluorescence only if iodine exits cells through CFTR channels. This assay allows determining whether a corrector of nonsense mutation is able to lead to the synthesis of functional CFTR protein

Secondary

Measure	Time frame	Description
Immortalization of patient cells	an average 12 months	Immortalization of patient cells will be attempted by transfection of construct expressing the origin-of-replication defective SV40 as described in Gruenert et al.,2004
Expression of the CFTR gene at the mRNA and protein level	less than 1 week.	—

Countries

France

Contacts

CONTACTAnne Prévotat, MD

anne.prevotat@chru-lille.fr03 20 44 59 48

CONTACTFabrice Lejeune, PhD

fabrice.lejeune@inserm.fr

PRINCIPAL_INVESTIGATORAnne Prévotat, MD

University Hospital, Lille

Outcome results

None listed

Source: ClinicalTrials.gov · Data processed: May 23, 2026