Cystic fibrosis gene therapy trials and tribulations

Abstract

Cystic fibrosis (CF) has long been seen as a candidate for treatment by gene therapy. Reasons for this include: the genetics of CF are simple; it is an autosomal recessive disorder caused by mutations in a single gene, cystic fibrosis transmembrane conductance regulator (CFTR); only symptomatic treatments are currently available; the lung, the principal organ affected by CF, is accessible; and less than 100% gene transfer might still modulate the disease process. The cloning of the CFTR gene in 1989 led rapidly to clinical studies testing gene therapy for CF, but even the potential for a therapeutic benefit using this approach has proven somewhat harder to achieve than was perhaps initially foreseen.Over the past eight years, approximately 12 independent CF gene-therapy clinical trials have been reported, testing different delivery systems, target sites and routes of administration and assay systems. These studies have described variable degrees of gene transfer, functional correction, and adverse clinical findings. To add to this list are two new clinical studies that, although still not giving clear guidance as to an optimal approach, do continue to stimulate hope for gene transfer as a therapeutic approach for CF. They also demonstrate the problems that have beset researchers trying to move this technology from the laboratory to the clinic. Joseph et al.1xAerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. I. Methods, safety, and clinical implications. Joseph, P.M. et al. Hum. Gene Ther. 2001; 12: 1369–1382Crossref | PubMed | Scopus (62)See all References1 and Perricone etal.2xAerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. II. Transfection efficiency in airway epithelium. Perricone, M.A. et al. Hum. Gene Ther. 2001; 12: 1383–1394Crossref | PubMed | Scopus (54)See all References2 describe a multi-center clinical trial that assessed an adenoviral vector expressing the CFTR gene administered by bronchoscopy and/or aerosol. Rutz et al.3xA clinical inflammatory syndrome attributable to aerosolized lipid–DNA administration in cystic fibrosis. Ruiz, F.E. et al. Hum. Gene Ther. 2001; 12: 751–761Crossref | PubMed | Scopus (125)See all References3 report on a clinical trial assessing an aerosolized complex of plasmid DNA encoding the CFTR gene and a cationic lipid. Both studies report the presence of vector-derived CFTR mRNA, but only in a limited number (∼30–60%) of respiratory epithelial brushing samples available for testing. Interestingly, Perricone et al.2xAerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. II. Transfection efficiency in airway epithelium. Perricone, M.A. et al. Hum. Gene Ther. 2001; 12: 1383–1394Crossref | PubMed | Scopus (54)See all References2 estimated that the maximum of percentage of cells positive for the CFTR adenovirus vector was less than or equal to 2.4%; cell culture experiments have estimated that at least 5% of an epithelial cell layer must express CFTR to obtain a functional effect.These studies also demonstrate an important clinical problem that has been noted in some, but not all, previous trials: a transient inflammatory response (characterized by muscle and joint pain and fever) against the gene delivery vehicle in a significant proportion of individuals. So, is there still hope for CF gene therapy? Overall, yes; gene transfer has been clearly demonstrated in most of the trials conducted over the past few years and in these most recent studies, but it is likely that a significant improvement in gene-transfer efficiency will be needed in pre-clinical studies before new trials will be initiated.