Clinical trial NCT03670472: 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
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Cystic Fibrosis
Keywords: Cystic fibrosis
nonsense mutations
CFTR gene
nasal epithelial cells
nonsense mutation readthrough
Lead sponsor: University Hospital, Lille
Sponsor class: OTHER
Collaborators: name: Vaincre la Mucoviscidose
First posted: 2018-09-13
Enrollment: 85
Sex: ALL
Minimum age (years): 8
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with cystic fibrosis and carry a nonsense mutation on the 2 alleles of the gene coding for the CFTR channel.

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.


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

Primary outcomes:
measure: Transport of iodide ions through the CEVAS membrane
timeFrame: less than 48hrs after the collect.
Secondary outcomes:
measure: Immortalization of patient cells
timeFrame: an average 12 months
measure: Expression of the CFTR gene at the mRNA and protein level
timeFrame: less than 1 week.
Other outcomes:
Locations:
city: Amiens
country: France
facility: Camsp Chu Amiens
city: Bron
country: France
facility: Hopital Femme Mere Enfant - Hcl - Bron
city: Lille
country: France
facility: Hôpital Calmette,CHU
city: Marseille
country: France
facility: Aphm Hopital La Timone - Marseille
city: Montpellier
country: France
facility: Chu Montpellier
city: Paris
country: France
facility: Cmp Enfants Aphp Robert Debre - Paris
city: Paris
country: France
facility: Hu Paris Centre Site Cochin Aphp - Paris 14
city: Strasbourg
country: France
facility: Hopitaux Universitaires de Strasbour
Study officials:
affiliation: University Hospital, Lille
name: Anne Prévotat, MD
role: PRINCIPAL_INVESTIGATOR
References: