Physical and biological barriers to viral vector-mediated delivery of genes to the airway epithelium.

A gene therapy for cystic fibrosis (CF) lung disease by intralumenal delivery of therapeutic transgenes into the lung is a logical treatment strategy if efficient gene transfer can be achieved without detrimental effects to the patient. Indeed, pioneering work in the late 1980s showed that genetically engineered viruses could deliver the CF corrective transgene to cultured cells from patients with CF. However, after many attempts to deliver the corrective gene to the lungs of patients with CF in vivo and with the luxury of 20/20 hindsight, it is realized that although logical, the strategy to accomplish this task did not appreciate the evolution of the lung to resist invasion by pathogens such as viruses. It is now apparent that several levels of barriers exist that restrict exogenous gene delivery to the airway epithelium by commonly used viral vectors. Components of the innate and cell-mediated immune system collectively limit both the access to and duration of gene transfer vectors to the airway epithelium. Alternative viral vectors that have evolved to circumvent these barriers will require further development if gene transfer is ever to be considered a therapy for CF lung disease.