Correction of Nonsense Mutations in Cystic Fibrosis

Official title

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

Overview

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

• Other smear of nasal fossae
  1 smear of nasal fossae during a usual or scheduled visit

Primary outcome measures

• Transport of iodide ions through the CEVAS membrane [Time frame: less than 48hrs after the collect.]

Secondary outcome measures (2)

• Immortalization of patient cells [Time frame: an average 12 months]
• Expression of the CFTR gene at the mRNA and protein level [Time frame: less than 1 week.]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Case-control

Study locations

France · 8 centers

• Camsp Chu Amiens — Amiens
• Hopital Femme Mere Enfant - Hcl - Bron — Bron
• Hôpital Calmette,CHU — Lille
• Aphm Hopital La Timone - Marseille — Marseille
• Chu Montpellier — Montpellier
• Cmp Enfants Aphp Robert Debre - Paris — Paris
• Hu Paris Centre Site Cochin Aphp - Paris 14 — Paris
• Hopitaux Universitaires de Strasbour — Strasbourg

Identifiers

NCT: NCT03670472 · 2013_59 · 2014-A01236-41

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗