10.2 Gene Therapy for Cystic Fibrosis

Cystic fibrosis is an autosomal recessive disease, located on chromosome number 7. It is responsible for the cystic fibrosis transmembrane conductance regulator (CFTR). This is an CAMP-medicated chloride channel protein, that regulates ion channels (Riordan,et al1989 and Rommens,etal1989). The cause of mortality of CF, is a pulmonary disease, due to the accumulation of viscous mucus in the lung Smith et al 1996). This facilitates chronic bacterial infection, airway inflammation and premature death at around 29 years of age.

Current treatment of cystic fibrosis showed no improvement in survival rate. Therefore gene therapy could be a potential way to correct the biochemical abnormality. Since the lung is the primary target for CF gene therapy. It involves the introduction of the wild type (normal) CFTR gene into the airway epithelial cells. The introduction of the normal CFTR gene in cultured CF airway epithelial cell lead to restoration of normal chloride ion transport (Rich et al 1990,Wagner, and Gardener1997). However, the results showed that only 6 to 10% of CF airway epithelial cells can restore normal chloride transport properties, (Johnson,et al 1995). Another experiments carried out using adenoviral vectors to human CF bronchial xenografts, showed also only 5% of the cells completely restored chloride transport. These previous studies have provided the way for delivering the CFTR gene to intact airways first in animal models, followed by human clinical trials, based on nasal or and lung-directed gene transfer.

CF gene therapy at the moment uses Adenoviruses, Adeno-associated viruses and liposomes to achieve gene transfer via the airway epithelia resulting in at least partial correction of the chloride transport defect.  However, there are still several problems with these systems, which needs to be overcome.  Initial human clinical trials showed that the efficiency of gene transfer using viral vectors to uninjured airway epithelia by the present vectors is low.  It was found that the inefficiency of gene transfer using the adenovirus vectors to fully differentiated epithelial cells is due to the paucity of the cellular receptors required for internalization of the virus (Goldman, and Su, 1996)

Another problem in gene therapy using viral vectors is its safety since a number of adenoviral particles cause direct viral toxicity. Further problem with the use of adenoviral vectors for CF gene therapy is that host cellular and humoral immune response result in transient expression of the delivered gene (Wilson ,1995)