Interest of Gentamicin-induced Readthrough in Cystic Fibrosis Patients - Full Text View

Purpose

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	Intervention	Phase
Cystic Fibrosis	Drug: Gentamicin	Phase 2


Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Application of Functional Electrophysiological Tests to Evaluate Pharmacological Treatments in Patients With Cystic Fibrosis

Resource links provided by NLM:

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

Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:

CFTR-dependant chlorate secretion

Secondary Outcome Measures:

CFTR expression in nasal cells
Clinical beneficial effects


Estimated Enrollment:	20
Study Start Date:	January 2003
Estimated Study Completion Date:	June 2005

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.

Eligibility


Genders Eligible for Study:	Both
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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Please refer to this study by its ClinicalTrials.gov identifier: 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	AP-HP

More Information

No publications provided


ClinicalTrials.gov Identifier:	NCT00376428 History of Changes
Other Study ID Numbers:	02-03-10
Study First Received:	September 13, 2006
Last Updated:	February 24, 2015
Health Authority:	France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Assistance Publique - Hôpitaux de Paris:


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

Additional relevant MeSH terms:


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

ClinicalTrials.gov processed this record on February 25, 2015