Leonard, Anissa
[UCL]
Cystic Fibrosis (CF) is the most common severe genetic disease among the Caucasian population. It is caused by mutations in the gene encoding the CFTR protein. CFTR is a c-AMP regulated anion channel expressed in the airways, intestine, pancreas and other epithelias. In the respiratory tract, CFTR is expressed at the apical pole of many bronchial, bronchiolar and alveolar cells. Loss of CFTR impairs electrolytes transport, causing hyperviscous mucus and a loss of pulmonary host defense due to impaired mucociliary clearance of bacteria. Nasal transepithelial ion transport generates a potential difference which is measurable and characteristic in CF patients. This test has long been used to assist in the diagnosis of atypical CF and CFTRopathies. More recently, it has been used as an outcome measure in clinical trials of new CF therapies. The technique is tricky. It is applicable in animal models and in humans. The expertise is rare in the field requiring dedicated equipment, supplies and well trained operators. This thesis aims at evaluating the potential and /or limitations of nasal potential difference (NPD) test as an effective tool to measure treatment effect in CF. The first objective of the thesis is to evaluate the therapeutic efficacy of miglustat in F508del homozygous CF patients using NPD as a primary endpoint. With the development of multicenter clinical trials around the world, an urgent need of standardizing the NPD test has emerged. A standardized operating protocol(SOP)has been validated and adopted by CF centers worldwide. However, data on reproducibility of this method in CF patients is missing. While practicing bench-to-bedside translational research, the second objective of the thesis is to compare variability of the NPD test in humans and mice using the latest SOP. A further objective of the thesis is to evaluate repeatability of TCS measurements with the latest SOP in CF patients homozygous for the F508del mutation in two different CF centres with two skilled and certified operators.
Bibliographic reference |
Leonard, Anissa. Nasal potential difference test for detection of treatment response in cystic fibrosis. Prom. : Lebecque, Patrick ; Lebacq, Jean |
Permanent URL |
http://hdl.handle.net/2078.1/144617 |