oa Editorial [Hot Topic: New Developments in Pharmaceutical Treatments for Cystic Fibrosis (Executive Guest Editor: Hartmut Grasemann)]

Cystic fibrosis (CF) is an inherited disease of impaired epithelial transmembrane ion transport which is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Conventional treatment strategies for CF lung disease, the major contributor to morbidity and mortality in patients with CF, are predominantly symptomatic and do not address the underlying defects. A better understanding of the biological consequences of CFTR gene mutations has lead to the development of new therapies aiming to correct specific aspects of CFTR dysfunction. These drugs include osmotically active agents but also CFTR pharmacotherapeuticals. In this issue, new CF therapies that are in pre-clinical and clinical testing are reviewed by Ratjen and Grasemann [1]. CFTR pharmacotherapeuticals include chemical compounds that result in improved folding and biosynthetic maturation of mutated CFTR or promote proper ion channel function in dysfunctional CFTR protein that is expressed at the cell surface. The use of high throughput screens for the detection of potential CFTR pharmacotherapeuticals is reviewed by Pasyk and coworkers [2]. An update on developments in the field of gene therapy for CF using gene transfer as well as cell therapy-based approaches including the administration of stem cells or progenitor cells is given by Griesenbach and Alton from the UK Cystic Fibrosis Gene Therapy Consortium. [3] With new therapies in clinical testing that aim to improve CFTR expression and function there is a growing need for sensitive and reliable tests that can be used to measure treatment effects on transepithelial ion transport. Currently available in vivo tests as well as new methods and their potential application in the assessment of effectiveness of therapeutic interventions are reviewed by Gonska [4]. CF lung disease severity is not closely related to the CFTR genotype. Phenotypic variability and the lack of genotype-phenotype correlation amongst unrelated patients with the same CFTR mutations and even amongst siblings that carry identical mutations and share a similar environment has led to the suggestion that genes other than CFTR may modify the course of the disease. A better understanding of the disease modifying pathways may lead to the identification of new therapeutic targets. Advances in this field are reviewed by Dorfman [5]. Infection of the CF lung with opportunistic organisms results in progressive loss of pulmonary function and ultimately respiratory failure. Typical early CF pathogens include Staphylococcus aureus and Haemophilus influenzae. Infections with Pseudomonas aeruginosa, which initially are non-mucoid and potentially eradicable, can become chronic when the pathogen switches phenotype to mucoid forms. Chronic infections with Pseudomonas have been shown to significantly contribute to lung disease progression in patients with CF. Early and aggressive treatment of infections with systemic or inhaled antibiotics are thought to be one of the major contributors to improved outcomes in CF populations. New developments in the area of inhaled antibiotics for the treatment of Pseudomonas aeruginosa are summarized by Hofmann [6] and an overview of new treatments for emerging CF pathogens other than Pseudomonas is given by Waters [7]. The production of nitric oxide (NO) is reduced in CF airways. As NO, among other functions, is a mediator of smooth muscle tone and thought to be important in host defense against certain pathogens, low NO may contribute to airways obstruction and infection of the CF lung. Grasemann and Ratjen here review the current understanding of the reasons and consequences of impaired L-arginine/NO metabolism in CF and how this knowledge may lead to new CF therapies [8]. Lung transplantation is accepted life saving therapy in CF patients with severe advanced lung disease and results in improved health-related quality of life. However, survival following lung transplantation remains less favorable compared to transplantation of other solid organs. Prevention and treatment of early and late transplant-related complications may help to further improve the outcome in lung transplantation recipients. New developments in the treatment after lung transplantation are critically reviewed by Benden and colleagues [9]. In summary, in this special issue of Current Pharmaceutical Design, a group of international experts summarizes and discusses new developments in the pharmaceutical treatment of patients with cystic fibrosis. I would like to thank the authors of this special issue for their contributions.