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Will all patients with Cystic Fibrosis benefit from the development of…
Will all patients with Cystic Fibrosis benefit from the development of CFTR correctors and potentiators
What is CF?
A genetically inherited disease caused by a defect in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) - a chloride ion channel expressed in all epithelial cells.
Imbalance of ion regulation leads to dehydration and acidification of epithelial lining as well as increased mucin polymer cross-links, raise the amount and viscosity of mucus in the gel phase, meaning the mucus cannot be removed by ciliary beating so accumulates.
Accumulation of mucus leads to airway obstruction, broncheatitis and inflammation.
Frequently pathogens colonize the airways and increase the recruitment of inflammatory cells.
Oxygen depletion below the sputum-air interface favors biofilm formation.
The destruction of airway and lung parenchyma epithelial cells causes tissue remodeling, reduction of gas exchange area and impairment of lung function.
As the disease progresses, the patient succumbs to death due to respiratory failure. (b)
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First-generation modulators
Ivacaftor and lumacaftor are called first-generation modulators because they were the first modulators approved for treating CF.
Tezacaftor, which was approved in Feb 2018 is also considered a first-generation modulator. (a)
New-generation modulators Elexacaftor is considered to be a next-generation modulator, which are potentially more effective than first-generation CFTR modulators, others are in development.
They are likely to be part of a triple combination therapy to provide more people with CF a variety of treatment options. Having alternatives is important as patients respond differently to drugs and not all patients can take currently approved modulators due to side effects, drug interactions or having mutations which aren't responsive.
Each of the three drugs in a triple-combination therapy addresses different aspects of the defective CFTR protein. (a)
DeltaF508 mutation causes reduced thermal and kinetic stability of NBD1 and precludes interdomain interactions so ER retains the misfolded CFTR which forms only a partially glycosylated protein, and the proteasome promptly degrades it.(b)