The characterization of Cystic Fibrosis (CF)-associated gene, in 1989, had two immediate consequences: 1. the path to gene therapy was opened; 2. the possibility of studying the CF base defect with new tools and in a completely original perspective. Greatest progresses have been obtained in understanding the gene product (the CFTR protein) function and in disclosing the cellular mechanisms through which gene mutations lead to biochemical defect. Current molecular biology and pharmacology knowledge provide the chance of intervening at different levels into the complex processes of biosynthesis and/or activation, so to recover the activity of mutated CFTR. Nowadays, a vast array of possible pharmacological treatments, intended to rescue, alone or in combination, all or part of the CFTR activity, can be devised. Aminoglycosides, for instance, are known to interfere with mechanisms of protein synthesis interruption. Recently was shown that aminoglycosides can overcome the CFTR synthesis blockade due to "nonsense" mutations, both in vitro and in vivo. Most frequent CF-associated mutations cause a defect of intracellular CFTR processing, and mutated CFTR accumulates in the Golgi apparatus: compounds facilitating intracellular processing may restore CFTR activity. Among these compounds, phenylbutyrate has been approved for inborn errors of metabolism therapy and is currently evaluated in ongoing clinical trials. Many compounds turned out to be able of activating CFTR and can be used to recover some activity of the mutated protein. At the moment, the possibility of an efficient pharmacological treatment of CF depends on the combination of different drugs with a synergistic effect. Such treatment can possibly be combined also with the use of other drugs modifying the activity of other membrane channels, in order to compensate for the CFTR defect. Preliminary data are encouraging: further studies will open the path of a pharmacological therapy for CF.
|Translated title of the contribution||Prospectives of pharmacological correction of CFTR deficiency in Cystic Fibrosis|
|Number of pages||9|
|Publication status||Published - 2001|
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health