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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
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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
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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

MedlinePlus related topics: Cystic Fibrosis

Arms and Interventions
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Outcome Measures
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Primary Outcome Measures :
  1. CFTR-dependant chlorate secretion

Secondary Outcome Measures :
  1. CFTR expression in nasal cells
  2. Clinical beneficial effects

Eligibility Criteria
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Ages Eligible for Study:   Child, Adult, Older Adult
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
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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
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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