Gene therapy for cystic fibrosis lung disease: overcoming the barriers to translation to the clinic

Abstract

Cystic fibrosis (CF) is a progressive, chronic and debilitating genetic disease caused by mutations in the CF Transmembrane-Conductance Regulator (CFTR) gene. Unrelenting airway disease begins in infancy and produces a steady deterioration in quality of life, ultimately leading to premature death. While life expectancy has improved, current treatments for CF are neither preventive nor curative. Since the discovery of CFTR the vision of correcting the underlying genetic defect - not just treating the symptoms - has been developed to where it is poised to become a transformative technology. Addition of a properly functioning CFTR gene into defective airway cells is the only biologically rational way to prevent or treat CF airway disease for all CFTR mutation classes. While new gene editing approaches hold exciting promise, airway gene-addition therapy remains the most encouraging therapeutic approach for CF. However, early work has not yet progressed to large-scale clinical trials. For clinical trials to begin in earnest the field must demonstrate that gene therapies are safe in CF lungs; can provide clear health benefits and alter the course of lung disease; can be repeatedly dosed to boost effect; and can be scaled effectively from small animal models into human-sized lungs. Demonstrating the durability of these effects demands relevant CF animal models and accurate and reliable techniques to measure benefit. In this review, illustrated with data from our own studies, we outline recent technological developments and discuss these key questions that we believe must be answered to progress CF airway gene-addition therapies to clinical trials.