Is gene therapy in cystic fibrosis a realistic expectation?

To date there are 11 human protocols either ongoing or approved for gene therapy for cystic fibrosis (CF) in the United States. There are also two protocols in the United Kingdom and one in France. Of these, results have been published in four. The protocols vary in the cells targeted, the vectors used, and the frequency of administration, but despite these differences all have contributed toward answering the key questions that will determine the future of gene therapy for CF: the questions of efficacy and safety. These studies have demonstrated that it is feasible to transfer the normal human CF transmembrane conductance regulator complementary DNA to the respiratory epithelium and that this will lead to production of normal CF transmembrane conductance regulator protein and in some cases to a physiologic response. The most frequently used vector is the adenovirus. Obstacles to be overcome with this system include the need for improved and prolonged expression, efficacy on repeat administration, and decreased inflammation. Recent work on the immune response to adenoviral vectors may help achieve these goals. The cationic lipid method of gene delivery is less likely than adenovirus to cause inflammation, at least in the nose, but improved efficacy of gene transfer is necessary as well as improved complex stability. Furthermore, this system has yet to be tested in the lungs of individuals with CF. Finally, the adeno-associated virus, the other vector approved for human gene therapy studies in CF, has shown some promise in preclinical studies but remains to be tested in humans. The results of these studies give some cause for guarded optimism, but point out a number of problems that must be overcome before gene therapy for CF delivers on the promise of a safe effective treatment for this condition.