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Questions and Answers
What is the primary function of the CFTR protein?
What is the primary function of the CFTR protein?
- To produce mucus in the respiratory tract
- To facilitate the transport of Cl- and HCO3- ions across the epithelial cell membrane (correct)
- To transport amino acids across the cell membrane
- To regulate the expression of genes involved in cystic fibrosis
What is the normal range of Cl- concentration in sweat for a healthy individual?
What is the normal range of Cl- concentration in sweat for a healthy individual?
- Greater than 60 mM
- Between 40-60 mM
- Less than 60 mM (correct)
- Less than 40 mM
Which of the following domains is NOT a component of the CFTR protein?
Which of the following domains is NOT a component of the CFTR protein?
- Intracellular nucleotide-binding domain
- Transmembrane segment
- Intracellular regulatory domain
- Extracellular ligand-binding domain (correct)
What is the genetic location of the CFTR gene?
What is the genetic location of the CFTR gene?
What is the purpose of the sweat test in diagnosing cystic fibrosis?
What is the purpose of the sweat test in diagnosing cystic fibrosis?
What is the primary function of Ivacaftor (VX-770) in the context of cystic fibrosis?
What is the primary function of Ivacaftor (VX-770) in the context of cystic fibrosis?
In the Ussing chamber experiment, what is the purpose of amiloride?
In the Ussing chamber experiment, what is the purpose of amiloride?
According to the study by Van Goor et al., what can be inferred about the effectiveness of Ivacaftor?
According to the study by Van Goor et al., what can be inferred about the effectiveness of Ivacaftor?
What is the purpose of forskolin in the Ussing chamber experiment?
What is the purpose of forskolin in the Ussing chamber experiment?
What is the genetic background of the bronchial epithelial cells used in the Ussing chamber experiment?
What is the genetic background of the bronchial epithelial cells used in the Ussing chamber experiment?
What is the primary function of CFTR in the bronchial epithelium?
What is the primary function of CFTR in the bronchial epithelium?
What is the effect of PKA phosphorylation on the CFTR regulatory domain?
What is the effect of PKA phosphorylation on the CFTR regulatory domain?
In which year was Trikafta approved by the EMA?
In which year was Trikafta approved by the EMA?
What is the predicted increase in median survival for patients with CF treated with Trikafta between the ages of 12 and 17 years?
What is the predicted increase in median survival for patients with CF treated with Trikafta between the ages of 12 and 17 years?
What is the consequence of impaired CFTR function in the respiratory tract?
What is the consequence of impaired CFTR function in the respiratory tract?
What is the role of adenylate cyclase in the cAMP signaling pathway?
What is the role of adenylate cyclase in the cAMP signaling pathway?
In which year was Trikafta approved by AIFA for prescription under the Italian public health service?
In which year was Trikafta approved by AIFA for prescription under the Italian public health service?
Who were the recipients of the 2024 Breakthrough Prize for the development of Trikafta?
Who were the recipients of the 2024 Breakthrough Prize for the development of Trikafta?
What is the defect in cystic fibrosis?
What is the defect in cystic fibrosis?
What is the name of Trikafta in the European market?
What is the name of Trikafta in the European market?
What is the effect of lumacaftor on F508del CFTR in vitro studies?
What is the effect of lumacaftor on F508del CFTR in vitro studies?
What is the primary outcome of the lumacaftor-ivacaftor clinical trial in CF patients?
What is the primary outcome of the lumacaftor-ivacaftor clinical trial in CF patients?
What is the difference between lumacaftor and other CFTR correctors?
What is the difference between lumacaftor and other CFTR correctors?
What type of assay was used to evaluate protein maturation in CF cell models?
What type of assay was used to evaluate protein maturation in CF cell models?
What is the advantage of combining lumacaftor with VX-770?
What is the advantage of combining lumacaftor with VX-770?
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Study Notes
Cystic Fibrosis Diagnosis
- A positive IRT test is followed by a sweat test and DNA test for clinical diagnosis.
- Sweat test measures Cl- and Na+ concentrations in sweat after stimulation with pilocarpine.
- In CF, sweat Cl- concentration is > 60 mM.
CFTR Gene and Protein
- The CFTR gene is located at 7q31.2 and codes for the CFTR protein.
- CFTR is an anion channel for Cl- and HCO3- expressed on the apical surface of epithelial cells in exocrine organs.
- The protein consists of 2 membrane spanning domains, 2 nucleotide-binding domains, and 1 regulatory domain.
CFTR Function
- CFTR is normally closed and opens following activation via the cAMP signaling pathway.
- Activation involves ligand binding to a membrane receptor, adenylate cyclase activation, and protein kinase A phosphorylation of the CFTR regulatory domain.
- This leads to a conformational change, pore opening, and chloride flux.
Respiratory Tract
- In bronchial epithelium, normal CFTR mediates Cl- efflux and limits Na+ reabsorption, maintaining airway surface liquid hydration.
- In CF, mutant CFTR leads to impaired mucociliary clearance, dehydration, and acidification of airway surface liquid.
CFTR Modulators
- Ivacaftor (VX-770) is a CFTR potentiator that increases Cl- transport.
- Lumacaftor (VX-809) is a CFTR corrector that increases F508del CFTR maturation and chloride secretion.
- Combined treatment with lumacaftor and ivacaftor improves lung function in CF patients.
Trikafta Treatment
- Trikafta is a combination of tezacaftor, ivacaftor, and elexacaftor approved for CF patients with F508del CFTR.
- Simulation models predict that Trikafta treatment increases median survival by 45.4 years compared to best standard care alone.
- Trikafta has been approved by the EMA and AIFA for prescription under the Italian public health service.
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