Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function
Fredrick Van Goor1, Haihui Yu2, Bill Burton2
1Vertex Pharmaceuticals Incorporated, 130 Waverly St, Cambridge, MA, United States; Vertex Pharmaceuticals Incorporated, 11010 Torreyana Road, San Diego, CA 92121, United States.
Summary
Ivacaftor is a broad-acting potentiator that enhances multiple cystic fibrosis transmembrane conductance regulator (CFTR) protein forms. This finding suggests ivacaftor may benefit a wider range of CFTR genotypes.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Ivacaftor (VX-770) is a CFTR potentiator effective for CF patients with the G551D mutation.
- It enhances CFTR channel activity and improves lung function in specific patient groups.
Purpose of the Study:
- To evaluate ivacaftor's effect on various mutant CFTR protein forms.
- To assess ivacaftor's impact on CFTR with processing and/or channel function defects.
Main Methods:
- In vitro electrophysiological studies were conducted.
- Fischer rat thyroid (FRT) cells expressing 54 missense CFTR mutations were utilized.
- The study assessed CFTR function at the cell surface.
Main Results:
- Ivacaftor demonstrated potentiation of multiple mutant CFTR protein forms.
- These potentiated forms exhibited functional CFTR at the cell surface.
- Mutant CFTRs with mild processing or conductance defects were responsive.
Conclusions:
- Ivacaftor acts as a broad-spectrum CFTR potentiator.
- In vitro data support its potential use in stratifying CF patients for clinical trials.
- This suggests broader applicability across different CFTR genotypes.
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