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Transformative therapies for rare CFTR missense alleles
Kathryn E Oliver1, Sangwoo T Han2, Eric J Sorscher1
1Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
Current Opinion in Pharmacology
|October 17, 2017
Summary
Understanding cystic fibrosis (CF) genotype-phenotype correlations is key. Research focuses on CFTR variants and developing modulator therapies like Ivacaftor and Lumacaftor to improve treatment.
Area of Science:
- Genetics and Molecular Biology
- Pharmacology
Background:
- Over 1900 variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are known.
- Cystic Fibrosis (CF) genotype-phenotype correlation is a critical research area.
- CFTR gating variants are targeted by potentiator drugs like Ivacaftor.
Purpose of the Study:
- To explore genotype-phenotype correlations in CFTR variants.
- To advance therapeutic strategies for CF, focusing on the F508del variant.
- To evaluate the efficacy of combined modulator therapies.
Main Methods:
- Review of existing literature on CFTR variants and genotype-phenotype correlations.
- Analysis of therapeutic approaches targeting CFTR dysfunction.
- In silico and in vitro modeling for variant characterization and drug testing.
Main Results:
- Ivacaftor is effective for specific CFTR missense variants impacting gating.
- Combination therapy with Ivacaftor and Lumacaftor shows modest improvement for F508del-CFTR.
- Lumacaftor aids in the maturational processing of misfolded CFTR.
Conclusions:
- Continued development of in silico and in vitro models is crucial for CF research.
- These models will aid in CFTR variant characterization and drug screening.
- Understanding molecular pathogenesis and modulator responsiveness is key to personalized CF treatment.