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.<sup>15 Collins F.S. Cystic fibrosis: Molecular biology and therapeutic implications Science 1992 ;  256 : 774-779

Cliccare qui per andare alla sezione Riferimenti</sup> Some investigators have also implicated CFTR in the transport of ATP, either directly or through a closely associated transporter.<sup>10 Cantiello H.F. Nucleotide transport through the cystic fibrosis transmembrane conductance regulator Biosci Rep 1997 ;  17 : 147-171  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 21 Devidas S., Guggino W.B. The cystic fibrosis transmembrane conductance regulator and ATP Curr Opin Cell Biol 1997 ;  9 : 547-552  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 56 Li C., Ramjeesingh M., Bear C.E. Purified cystic fibrosis transmembrane conductance regulator (CFTR) does not function as an ATP channel J Biol Chemother 1996 ;  271 : 11623-11626

Cliccare qui per andare alla sezione Riferimenti, 69 Schwiebert E.M., Egan M.E., Hwang T.H. , e al. CFTR regulates outwardly rectifying chloride channels through an autocrine mechanism involving ATP Cell 1995 ;  81 : 1063-1073  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> Third, independent laboratories have confirmed that CFTR directly inhibits the epithelial amiloride-sensitive sodium channel that coexists on the apical membrane.<sup>37 Ismailov I.I., Berdiev B.K., Shlyonsky V.G. , e al. Role of actin in regulation of epithelial sodium channels by CFTR Am J Physiol 1997 ;  272 : C1077-C1086

Cliccare qui per andare alla sezione Riferimenti, 53 Kunzelmann K., Kiser G.L., Schreiber R. , e al. Inhibition of epithelial Na+currents by intracellular domains of the cystic fibrosis transmembrane conductance regulator FEBS Lett 1997 ;  400 : 341-344  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> Fourth, CFTR directly stimulates the outwardly rectifying chloride channel (ORCC).<sup>42 Jovov B., Ismailov I.I., Benos D.J. Cystic fibrosis transmembrane conductance regulator is required for protein kinase A activation of an outwardly rectified anion channel purified from bovine tracheal epithelia J Biol Chem 1995 ;  270 : 1521-1528

Cliccare qui per andare alla sezione Riferimenti, 43 Jovov B., Ismailov I.I., Berdiev B.K. , e al. Interaction between cystic fibrosis transmembrane conductance regulator and outwardly rectified chloride channels J Biol Chem 1995 ;  270 : 29194-29200

Cliccare qui per andare alla sezione Riferimenti, 69 Schwiebert E.M., Egan M.E., Hwang T.H. , e al. CFTR regulates outwardly rectifying chloride channels through an autocrine mechanism involving ATP Cell 1995 ;  81 : 1063-1073  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> 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.<sup>31 Goldman M.J., Anderson G.M., Stolzenberg E.D. , e al. Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis Cell 1997 ;  88 : 553-560  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 51 Ko Y.H., Delannoy M., Pedersen P.L. Cystic fibrosis, lung infections, and a human tracheal antimicrobial peptide (hTAP) FEBS Lett 1997 ;  405 : 200-208  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 73 Smith J.J., Travis S.M., Greenberg E.P. , e al. Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid [published erratum appears in Cell 87:355, 1996] Cell 1996 ;  85 : 229-236  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> 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.