Background of the Study
The cause of cystic fibrosis is a mutation in the transmembrane conductance regulator. A new "corrector" called lumacaftor (VX-809) has been created to enhance CFTR trafficking and maturation, while ivacaftor (VX-770) aims to improve channel activity. These advancements have the potential to revolutionize cystic fibrosis treatment.
Ivacaftor (VX-770) has shown significant clinical efficacy in patients with the G551D mutation, which affects channel activity. However, treating patients with ?F508 mutations requires both potentiators and correctors to achieve clinical significance. The effectiveness of this drug combination has been demonstrated in vitro using human primary airway epithelial cells. Chronic and acute treatment with VX-770 has improved function in cells with the G551D mutation.
Study Relevance
This study aimed to understand the molecular mechanisms behind limited improvement in ?F508 CFTR function when combining a potentiator (VX-770) a
...nd a corrector (VX-809) for CF patient treatment.
The mutations in the transmembrane conductance regulator result in the transportation of CFTR-mediated chloride ions and hydro carbonate ions by absorptive and secretory epithelial cells in organs such as the pancreas, liver, and lungs. This leads to disturbances in the airways, resulting in the disruption of surface liquid homeostasis. As a consequence, thick mucus is produced, blocking the airways, causing inflammation, persistent infection, and a decline in lung function.
Hypothesis
The breakthrough in addressing the cause of cystic fibrosis came with the identification of the CFTR gene on chromosome 7 and its common mutation, ?F508 CFTR (4-6).
Discussion of the Data Collected
Potentiator compounds target the mutant CFTR channels that are present on the surface of epithelial cells. One pharmacological agent called VX-770 has been approved to treat CF patients.
The study demonstrates tha
VX-770 effectively restores CFTR chloride ion secretion in human bronchial epithelial cells from patients with the G551D mutation. The chronic use of VX-770 increases chloride ion secretion through G551D CFTR, but forskolin stimulation is required for activation. These findings support the use of cyclic-AMP raising ?2 adrenergic receptor agonists as a standard treatment for G551D CF patients who are receiving VX-770.
Questions Regarding the Method
The administration of VX-770 has shown to improve CFTR function in cell lines expressing G551D CFTR and enhance chloride ion secretion in primary human bronchial epithelial cells from cystic fibrosis patients. This study aims to compare the effects of chronic and acute administration of VX-770 in the airway epithelia of individuals with the G551D mutation.
Method Facilitating Conceptual Understanding
To comprehend the concept, samples underwent immunoprecipitation and western blotting using a 4 to 20% gradient SDS-PAGE gel. Subsequently, these separated samples were transferred onto a nitrocellulose membrane.
The blots were tested using mouse monoclonal anti-CFTR antibodies and then IR Dye 680-goat anti mouse igG. Controls such as anti-actin and anti-tubulin were employed. The protein bands were visualized using the Odyssey Infrared Imaging System.
Conclusion Derived From the Study
The statistical analysis indicates that the average response per primary human bronchial epithelial cell donor, along with error bars representing the standard error for the mean.
P values below 0.05 are deemed statistically significant.
Evidence supporting the conclusion
The VX-809 seems to restore around 15% of normal function in ?F508/?F508 CF HBE cells. However, overcoming CF symptoms requires approximately 25% CFTR function.
Study limitations
Finding significant results takes a considerable amount of time.
Furthermore, the research involves using advanced equipment that is both
difficult to obtain and maintain.
Debate within the Study
Many may have assumed that airway obstruction is caused by exposure to physical environmental factors like cold. However, certain blockages are actually a result of gene mutations in the human genome.
The examined article focuses on cystic fibrosis, which is a genetic disease. On the other hand, the alternative article discusses inherited genetic diseases such as kidney disease, blood brain barrier dysfunction, and biofilms.
