Interest of Gentamicin-induced Readthrough in Cystic Fibrosis Patients

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ClinicalTrials.gov Identifier: NCT00376428

Recruitment Status : Terminated

First Posted : September 14, 2006

Last Update Posted : February 25, 2015

Sponsor:

Information provided by:

Assistance Publique - Hôpitaux de Paris

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis	Drug: Gentamicin	Phase 2

Detailed Description:

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.

Study Design


Study Type :	Interventional (Clinical Trial)
Enrollment :	20 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Application of Functional Electrophysiological Tests to Evaluate Pharmacological Treatments in Patients With Cystic Fibrosis
Study Start Date :	January 2003
Study Completion Date :	June 2005

Resource links provided by the National Library of Medicine

Genetics Home Reference related topics: Cystic fibrosis

MedlinePlus related topics: Cystic Fibrosis

Drug Information available for: Gentamicin Gentamicin sulfate

Genetic and Rare Diseases Information Center resources: Cystic Fibrosis

U.S. FDA Resources

Arms and Interventions

Outcome Measures

Primary Outcome Measures :

CFTR-dependant chlorate secretion

Secondary Outcome Measures :

CFTR expression in nasal cells
Clinical beneficial effects

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	Child, Adult, Senior
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00376428

Locations


France
Necker-Enfants malades
Paris, France, 75015

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Investigators


Study Director:	Aleksander Edelman, PhD	Institut National de la Santé Et de la Recherche Médicale, France
Principal Investigator:	Isabelle Sermet, MD; PhD	Assistance Publique - Hôpitaux de Paris

More Information


ClinicalTrials.gov Identifier:	NCT00376428 History of Changes
Other Study ID Numbers:	02-03-10
First Posted:	September 14, 2006 Key Record Dates
Last Update Posted:	February 25, 2015
Last Verified:	September 2006

Keywords provided by Assistance Publique - Hôpitaux de Paris:


Cystic Fibrosis Transmembrane Conductance Regulator Premature termination codon Gentamicin-induced readthrough

Additional relevant MeSH terms:


Fibrosis Cystic Fibrosis Pathologic Processes Pancreatic Diseases Digestive System Diseases Lung Diseases Respiratory Tract Diseases Genetic Diseases, Inborn	Infant, Newborn, Diseases Gentamicins Anti-Bacterial Agents Anti-Infective Agents Protein Synthesis Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action

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