Essais cliniques de thérapie génique de la mucoviscidose : état des lieux et perspectives.

Abstract

La caractérisation du gène CFTR et la démonstration in vitro que le transfert du gène CFTR normal dans des cellules issues de patients atteints de mucoviscidose corrige les anomalies de transport ionique ont encouragé de nombreuses équipes à envisager la thérapie génique comme une voie thérapeutique permettant de s’attaquer à la cause de la maladie. Vingt-six protocoles cliniques ont été à ce jour mis en oeuvre dans le monde. Ces protocoles visent à évaluer, soit un mode d’administration particulier du vecteur de transfert de gène, soit un vecteur bien défini. Aujourd’hui, une nouvelle génération de vecteurs moins toxiques et permettant une bonne persistance in vivo de l’expression du transgène est disponible. De la même manière, de nouvelles molécules polycationiques ont été récemment développées et sont actuellement en évaluation préclinique. L’avenir de la thérapie génique de la mucoviscidose dépendra du succès de ces développements techniques, mais également de la meilleure maîtrise des méthodologies d’analyse des paramètres électrophysiologiques pulmonaires.

Since the cloning of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) in 1989, cystic fibrosis has been a privileged target 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 administered to the nose (instillation), to the maxillary sinus (instillation) and 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 information in terms of biological efficiency. They demonstrated the feasibility of an in vivo transfer and expression of the CFTR gene to the airway epithelium with in certain cases correction of functional parameters. They have also shown some limitations in the delivery systems (e.g. transient CFTR expression, modest number of transduced cells, inflammatory response to adenoviral 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 be 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 understand 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 synthetic vectors are now ready for the clinic, while novel vectors with potentially improved characteristics are under active development (e.g. lentivirus-derived vectors, adenovirus vectors deleted from all coding viral regions).