Cystic fibrosis: bench to bedside 2003.

Abstract

Department of Pediatrics, and Departments of Biomedical Engineering, Physiology and Pharmacology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, North Carolina, USA Correspondence: Dr Bruce K Rubin, Department of Pediatrics, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1081, USA. Telephone 336-716-0512, fax 336-716-9229, e-mail brubin@wfubmc.edu In the 17 years since the cystic fibrosis transmembrane ion regulator (CFTR) gene and protein were first identified at the Hospital for Sick Children in Toronto, Ontario (1), much has been learned about the primary defect in cystic fibrosis (CF) and how this relates to some of the clinical manifestations of this disease. The CFTR protein regulates airway chloride transport, and is also a regulator of sodium and water transport across the epithelium (2). In addition, it appears to play a role in the regulation of protein assembly and degradation within the cell (3). The complex regulatory network attributed to CFTR has made it difficult to link abnormalities of the gene and protein to the chronic airway infection and inflammation that are hallmarks of this disease. Thus, although the ‘cure’ for CF remains tantalizingly out of reach, new knowledge of disease pathogenesis and CFTR function has led to the development of novel therapies that have promise in controlling the relentless progress of lung disease (4). We have also learned that mild CFTR mutations can lead to a number of disorders now referred to as nonclassical CF (5). Some of these patients have chronic sinusitis and a later onset of chronic airway infection (6). Because of preserved exocrine pancreatic function, some patients develop pancreatitis in early adulthood (7). Sweat chloride values, usually in the range of 60 to 90 mmol/L, often are normal (8). Men with specific, mild CFTR defects can have no lung disease or pancreatic malabsorption, but only infertility with agenesis of the vas deferens and obstructive azoospermia (9). Because preservation of even a small amount of CFTR function appears to ameliorate lung disease, strategies have been proposed to augment abnormal CFTR function and enhance ion transport (10). This manuscript reviews some of the recently developed therapies for managing infection and inflammation in the CF airway, as well as progress toward correcting the abnormal chloride transport associated with CFTR protein malfunction, gene activation and gene replacement therapy, and finally the role of lung transplantation in end-stage CF lung disease.