THERAPIES DIRECTED AT THE BASIC DEFECT IN CYSTIC FIBROSIS - 09/09/11
Résumé |
In the past several years, there has been a small explosion of new ideas directed at treating the basic defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR). This translational research spans the molecular disciplines of gene transcription, protein translation, protein trafficking and degradation, chloride channel structure, conductance and regulation, alternative chloride channels, and cellular defense. Without the in-depth basic genetic research, the translational clinical benefits would not have been realized.
More than 600 unique mutations have been found in the cystic fibrosis (CF) gene, and they can be classified in five general categories with respect to CFTR. Elimination of CFTR production (class I), defects in folding or trafficking through the Golgi apparatus to the cell surface (class II), aberrant regulation of chloride conduction (class III), complete or partial inhibition of chloride conduction (class IV), and reductions in synthesis of a normal CFTR transcript (class V) can now be addressed in a genotype-specific manner. A new term has been coined to describe this novel concept— protein-repair therapy. This article reviews the latest developments in the area of novel therapeutics directed at the defective CFTR itself.
CFTR is a member of the adenosine triphosphate (ATP)-binding cassette superfamily that includes the well-studied multidrug resistant transporter (MDR). Representatives from this family of membrane glycoproteins can be found in yeast, insects, fish, and mammals. The common structural features are the two-fold symmetry of the molecule consisting of a six transmembrane domain unit anchored in the plasma membrane followed by a cytoplasmic ATP-binding fold that contains Walker A and B motifs. CFTR is unique among the other members with respect to a central regulatory (R) domain rich in phosphorylation sites for protein kinases A and C (PKA, PKC). This complex structure likely results in more than one function and, undoubtedly, different classes of mutations may affect one function more severely than another. Most investigations have confirmed that CFTR is primarily a c-adenosine monophosphate (cAMP)-regulated chloride channel that is normally found on apical membrane surfaces, where it regulates ion and fluid transport.15 Some investigators have also implicated CFTR in the transport of ATP, either directly or through a closely associated transporter.10, 21, 56, 69 Third, independent laboratories have confirmed that CFTR directly inhibits the epithelial amiloride-sensitive sodium channel that coexists on the apical membrane.37, 53 Fourth, CFTR directly stimulates the outwardly rectifying chloride channel (ORCC).42, 43, 69 Through one or more of these functions, CFTR plays an important role in the regulation of periciliary fluid composition in the upper and lower airways. The ionic composition of this fluid in turn appears to regulate the activity of one or more antimicrobial peptides that protect the airways from inhaled bacteria.31, 51, 73 A deeper understanding of the connection between specific classes of mutation in CFTR and functional consequences to the protein, the cell, and the epithelium will aid in the development of new therapeutics for CF. This article discusses each class of mutation and the current findings with respect to CFTR function, attempts to correlate aberrant function with disease pathogenesis, and reviews potential class-specific therapies under development.
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| Address reprint requests to Pamela Leslie Zeitlin, MD, PhD, Park 316, Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21287 |
Vol 19 - N° 3
P. 515-525 - septembre 1998 Retour au numéro
Article précédent
- THERAPIES AIMED AT AIRWAY INFLAMMATION IN CYSTIC FIBROSIS
- Michael W. Konstan
- IS DNA DESTINY? : A Cure for Cystic Fibrosis
- Cynthia B. Robinson
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