There are nearly 2,000 mutations in the CFTR gene, and only a small fraction of these have been tested for responses to approved drugs. CFTR modulators are small-molecule compounds that act upon CFTR by correcting a folding defect (VX-809) or by potentiating a gating defect (VX-770). Patients with gating mutations, like G551D, display very favorable responses to the drug, ivacaftor (VX-770). The far more common F508del mutation results in a protein that has a folding defect. 50% of CF patients have 2 copies of F508del and display modest responses to lumacaftor/ivacaftor (VX-809/VX-770). It is unknown if patients with rare mutations will respond to these CFTR modulators. In this workshop, we will discuss theratyping, which involves grouping patients who are likely to respond favorably to the same CFTR-modulating therapies (VX-809, VX-770, and novel compounds as they become available) based on their CFTR mutations. We will also discuss screening tools that may assist with theratyping.
Describe biomarkers and screening tools to identify compounds with improved potency and efficacy for F508del CFTR.
Explain how molecular and functional phenotypes of rare CFTR mutations will assist with identifying targets for drug therapies.
Discuss pre-clinical evidence for novel compounds that increase protein expression and function of mutant CFTR.