ABSTRACT
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). It is the commonest inherited disease, affecting 1 in 2500 live Caucasian births. The identification of the CFTR gene in 1989 (Kerem et al., 1989; Riordan et al., 1989; Rommens et al., 1989) combined with extensive physiological, microbiological and biochemical studies have provided a substantially greater understanding of the cellular and molecular biology underlying CF. In clinical terms, it is a multisystem disease, characterised by abnormal epithelial secretions. It is manifested in the lungs by obstruction and relentless damage to the airways with recurrent infections, in the gastrointestinal tract by exocrine pancreatic insufficiency leading to impaired digestion and bowel obstruction, in the liver by focal biliary cirrhosis, in the vas deferens by obstructive azospermia, and by excessive loss of salt via the sweat glands. However, the major cause of morbidity arises from complications of lung disease which result in the death of more than 95% of CF patients. There are diverse therapeutic options for CF airway disease. These include pharmacologic intervention to enhance the processing and functioning of the common mutant form of CFTR (Denning et al., 1992) or to correct the salt content in the airway surface fluid (Knowles et al., 1990), antiprotease therapy to decrease inflammation related damage (McElvaney et al., 1991), and the established antibiotic regimes for airways infection. Despite the progress being made in these conventional strategies the option of gene replacement therapy is particularly attractive since, theoretically, with one therapeutic intervention the myriad downstream effects of a mutant gene can be corrected. This is particularly true for CF since it is a monogenic disease and the target organ, the lung, is readily accessible. Vectors can be applied directly to airway epithelia without the need to harvest the target cells, modify them genetically and return them to the body. Rapid progress towards gene replacement has been made since the identification of the gene resulting in the first Phase 1a clinical trial in the nasal epithelium in 1991 (Zabner et al., 1993). However, within the next few years it became apparent that there were major difficulties in translating protocol and results from animal models to humans. In this chapter we will examine the progress made in CF gene therapy and the problems and issues highlighted by human clinical trials.
