The status of gene therapy for cystic fibrosis

Cystic fibrosis (CF) has been a primary focus for gene therapy of lung diseases because the genetic cause is known and the airway epithelium is accessible for direct deoxyribonucleic acid (DNA) delivery. Soon after the mutated gene was identified in 1989, investigators demonstrated that transfer of a normal copy of the CF gene corrected ion transport abnormalities, thus validating the potential for use of gene therapy for this autosomal recessive disease. However, subsequent studies in a variety of in vitro and animal models, and more limited human studies, have revealed several obstacles to gene therapy for CF: (1) The incomplete understanding of CF lung disease pathogenesis, particularly the relative importance of ion transport and other cellular abnormalities (including glycoconjugate processing, pH regulation of intracellular organelles, and membrane trafficking), and of surface epithelial versus submucosal gland CF transmembrane regulator (CFTR) expression, generates uncertainty as to the necessary target cells for gene transfer and the optimum end point(s) for short-term human studies. (2) The airway epithelium has protective barriers against viral infection that impair gene transfer with several vectors, including recombinant viruses and DNA conjugates. Improvement in DNA transfer technology will be necessary for successful gene therapy. (3) Immune responses to recombinant viruses and inflammatory effects of bacterial DNA are only partially understood and appear to limit efficacy, particularly with repeated administration. Identification of these obstacles is prerequisite for progress, and recent studies with novel DNA delivery methods appear promising.