Interest of Gentamicin-induced Readthrough in Cystic Fibrosis Patients

Study Overview
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Brief Summary
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Suppression of stop mutations in the CFTR gene with parenteral gentamicin can be predicted in vitro and is associated with clinical benefit and significant modification of the CFTR-mediated chloride transport in nasal and sweat gland epithelium.

Detailed Description
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Background: This study was conducted to determine whether intravenous gentamicin can suppress stop codons in cystic fibrosis (CF) patients and, if so, whether it has any clinical benefits. Methods: We first used a dual gene reporter system to determine the gentamicin-induced readthrough level of the most frequent CFTR stop mutations in the French population. We next investigated readthrough efficiency in response to 10 mg/kg once daily intravenous gentamicin perfusions in patients with stop mutations and in a control group of patients without stop mutations. Respiratory function, sweat chloride concentration, nasal potential difference (NPD) and CFTR expression in nasal epithelial cells were measured at baseline and after 15 days of treatment. Results: After in vitro gentamicin incubation, the readthrough efficiency for the Y122X mutation was at least five times higher than that for G542X, R1162X, and W1282X. In six of the nine patients with the Y122X mutation, CFTR immunodetection showed protein expression at the membrane of the nasal ciliated cells and the CFTR-dependent chloride secretion in their NPD measurements increased significantly. Respiratory status also improved in these patients, irrespective of the gentamicin sensitivity of the germs present in the sputum. Mean sweat chloride concentration decreased significantly and normalized in two patients. These measurements did not change in the Y122X patients with no protein expression, in patients with the other stop mutations investigated in vitro (n=4) and those without stop mutations (n=5). Conclusion: Suppression of stop mutations in the CFTR gene with parenteral gentamicin can be predicted in vitro and is associated with clinical benefit and significant modification of the CFTR-mediated chloride transport in nasal and sweat gland epithelium.

Official Title
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Application of Functional Electrophysiological Tests to Evaluate Pharmacological Treatments in Patients With Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Gentamicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: cystic fibrosis with CFTR codon stop mutations Exclusion Criteria: Rhinitis nasal polyposis passive or active smoking modification of basal treatments within the previous month treatments with aminoglycosides within three previous months
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Gentamicin|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CFTR-dependant chlorate secretion |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CFTR expression in nasal cells |  |  | 
| Clinical beneficial effects |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic Fibrosis Transmembrane Conductance Regulator, Premature termination codon, Gentamicin-induced readthrough