Title:Pharmacological Correction of Cystic Fibrosis: Molecular Mechanisms at the Plasma Membrane to Augment Mutant CFTR Function
Volume: 17
Issue: 11
Author(s): Kavisha Arora and Anjaparavanda P. Naren
Affiliation:
关键词:
囊性纤维化，F508del CFTR，F508del CFTR校正，CFTR的大分子复合物，个性化医学囊性纤维化，F508del CFTR，F508del CFTR校正，CFTR的大分子复合物，个性化医学
摘要: In the late 1980s, a loss-of-function mutation in the gene encoding for the cystic fibrosis
transmembrane conductance regulator (CFTR) chloride channel was identified to be the primary cause
of cystic fibrosis (CF); a fatal multiple-organ disorder that mostly affects Caucasians. To date, approximately
2000 genetic mutations have been identified in the CFTR gene
(http://www.genet.sickkids.on.ca/cftr/app). The most common cause of morbidity and mortality in persons
with CF is a progressive deterioration in lung function leading ultimately to respiratory collapse.
The median life expectancy of CF patients currently is estimated to be 39 years in the US. The most
prevalent CFTR mutation, F508del, accounts for 70% of CF cases and causes a processing defect in the protein leading to
premature endoplasmic reticulum-associated degradation (ERAD) and reduced F508del-CFTR delivery to the cell surface.
A CF corrector is defined as a chemical chaperone that increases cell-surface levels of F508del-CFTR. A series of CF correctors
have been developed, and VX-809 (lumacaftor) has been cited as the most effective symptomatic CF corrector to
date. VX-809 improves the function of the mutant protein by approximately 15% in in vitro culture systems. However,
this effect did not completely translate clinically, with only a marginal improvement observed in lung function of the
F508del-homozygous patients undergoing the therapy. New studies revealed that even after successful ER retrieval, rescued
F508del-CFTR (rF508del-CFTR) once at the cell surface does not function properly, exhibiting poor stability and
channel gating and structural abnormalities. This becomes further complicated by the existence of genes termed CFTR
modifiers, which can alter CFTR function to be additionally defective and exacerbate the CF phenotype while also alternatively
suggested be potentially targeted to improve F508del-CFTR functional outcome. It is necessary to understand the
biology of F508del-CFTR post-ER and at the plasma membrane where the protein might also confront the modifiers and
how we can incorporate these components into CF therapeutics. Additionally, the notion that CF individuals would eventually
benefit from more of a personalized medicine is becoming increasingly accepted. Here, we review how CF therapeutics
may be simplified by understanding the complexities of rescued F508del-CFTR biology and eventually move toward
more personalized medicine for patients suffering with CF.
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