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Sponsored by: |
Assistance Publique - Hôpitaux de Paris |
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Information provided by: | Assistance Publique - Hôpitaux de Paris |
ClinicalTrials.gov Identifier: | NCT00376428 |
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 |
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Cystic Fibrosis |
Drug: Gentamicin |
Phase II |
Study Type: | Interventional |
Study Design: | Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study |
Official Title: | Application of Functional Electrophysiological Tests to Evaluate Pharmacological Treatments in Patients With Cystic Fibrosis |
Estimated Enrollment: | 20 |
Study Start Date: | January 2003 |
Estimated Study Completion Date: | June 2005 |
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.
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
France | |
Necker-Enfants malades | |
Paris, France, 75015 |
Study Director: | Aleksander Edelman, PhD | Institut National de la Santé Et de la Recherche Médicale, France |
Principal Investigator: | Isabelle Sermet, MD; PhD | AP-HP |
Study ID Numbers: | 02-03-10 |
Study First Received: | September 13, 2006 |
Last Updated: | September 13, 2006 |
ClinicalTrials.gov Identifier: | NCT00376428 |
Health Authority: | France: Afssaps - French Health Products Safety Agency |
Cystic Fibrosis Transmembrane Conductance Regulator Premature termination codon Gentamicin-induced readthrough |
Digestive System Diseases Genetic Diseases, Inborn Respiratory Tract Diseases Cystic Fibrosis Fibrosis |
Lung Diseases Gentamicins Infant, Newborn, Diseases Pancreatic Diseases Cystic fibrosis |
Protein Synthesis Inhibitors Anti-Infective Agents Anti-Bacterial Agents Pathologic Processes |
Molecular Mechanisms of Pharmacological Action Therapeutic Uses Enzyme Inhibitors Pharmacologic Actions |