Gene therapy for cystic fibrosis: present status and perspectives

Since the cloning of the gene encoding the cystic fibrosis transmembrane co nductance regulator (CFTR) in 1989, cystic fibrosis has been a privileged t arget disease for gene therapy approaches. At present 26 clinical protocols involving CFTR gene transfer to airways have been completed or are ongoing . Three types of vectors have been used: adenovirus, adeno-associated virus and cationic lipids/plasmid complexes, Vector preparations have been admin istered to the nose (instillation), to the maxillary sinus (instillation) a nd to the lung (bronchofibroscopy, aerosol, endoscopic local spray). Doses were single or repeated. A part from few exceptions no adverse effects have been recorded so far. These trials have generated a great amount of inform ation in terms of biological efficiency. They demonstrated the feasibility of an in vivo transfer and expression of the CFTR gene to the airway epithe lium with in certain cases correction of functional parameters. They have a lso shown some limitations in the delivery systems (e.g. transient CFTR exp ression, modest number of transduced cells, inflammatory response to adenov iral vectors) and have addressed new questions to which we should answer in the next clinical trials (e.g. type of target cells?, number of cells to b e corrected to obtain therapeutic efficacy?, novel functional and clinical markers to define such therapeutic efficacy?). All this has been perceived by several laboratories which have undertaken major efforts to better under stand the biology of the vectors for gaining improvements in their safety, efficiency and production profile and to develop new assays for evaluating CFTR gene delivery and correction. New generation of adenovirus, AAV and sy nthetic vectors are now ready for the clinic, while novel vectors with pote ntially improved characteristics are under active development (e.g: lentivi rus-derived vectors, adenovirus vectors deleted from all coding viral regio ns).