Current Pharmaceutical Design - Volume 18, Issue 5, 2012

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.

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that lead to abnormalities in transepithelial ion transport in the airways of affected patients. Lung disease is the major contributor to morbidity and mortality in patients with cystic fibrosis but recommended therapeutic interventions so far have focussed on symptom control rather than treatment of the underlying causes of the disease. New therapies that are currently in pre-clinical and clinical testing include CFTR pharmacotherapy, drugs targeting other ion channels, and hydrators of the cystic fibrosis airways. The current status of these and other new developments in the treatment of cystic fibrosis are reviewed

These are exciting times with the appearance of small molecule compounds in clinical trials which target the basic defects caused by mutation in the CFTR gene. This progress was enabled by years of basic research probing the molecular and cellular consequences caused by mutation and the development of methods by which to study the primary anion transport defect in a high-throughput manner by robotics. Future progress with the development of new, more effective corrector compounds is needed. Such discovery will require further progress in defining the molecular targets for effective intervention using a multidisciplinary approach, merging computational, molecular, proteomic and cell biological methods. There is also an urgent need to develop means to link the right therapeutic compound to the right patients given the heterogeneity of the CF patient population. We envision a time when mid to high-throughput methods will be married with stem cell biology to enable testing a compendium of compounds on cells derived from each individual patient. Given the rate of progress in this field- this scenario may exist in the not too distant future.

Although the development of gene therapy for cystic fibrosis (CF) was high priority for many groups in academia and industry in the first 10 to 15 years after cloning the gene, more recently active research into CF gene therapy is only being performed by a small number of committed, mainly academic, groups. However, despite the waning enthusiasm, which is largely due to the realisation that gene transfer into lungs is more difficult than originally thought and the fact that meaningful clinical trials are expensive and difficult to perform, gene therapy continues to hold promise for the treatment of CF lung disease. Problems related to repeat administration of adenovirus and adeno-associated virus-based vectors led to a focus on non-viral vectors in clinical trials. The UK CF Gene Therapy Consortium is currently running the only active gene therapy programme, aimed at assessing if repeated administration of a non-viral gene transfer agent can improve CF lung disease. However, the recent suggestion that lentiviral vectors may be able to evade the immune system and, thereby, allow for repeat administration and long lasting expression opens new doors for the use of viral vectors in the context of CF gene therapy. In addition, early pre-clinical studies have recently been initiated to address cell therapy-based approaches for CF. This involves systemic and topical administration of a variety of stem/progenitor cells, as well as first attempts as producing a tissue-engineered lung. Recent studies in viral and non-viral vector developments, as well as cell therapy will be discussed and an update on clinical gene therapy studies will be provided here.

New therapeutic strategies are targeting correction of the basic defect in cystic fibrosis (CF) disease. In fact, completion of the first successful clinical drug trials now signals the start of a new era in CF therapy. Many promising drug candidates are emerging into the clinical drug pipeline. However, their translation from the bench to the bed side is challenged by the lack of accurate and reliable biomarker assays that allow testing for their clinical efficiency and safety in early clinical trials. It is surprising that despite the availability of modern equipment and technologies relatively little effort has been directed towards innovative approaches to exploit our pathophysiological understanding of CF disease for the design of novel assays that allow in vivo assessment of CFTR dysfunction as the measurable correlate of the basic defect of CF disease. This lack of adequate outcome measure is now gaining increased attention, and first studies are being initiated to screen larger CF patient cohorts for biological markers that can be used as a potential measure of drug response. This paper reviews currently available in vivo tests, highlighting new methods and their potential use as early in vivo markers for therapeutic investigations. Finally, key criteria of the validation process that needs to be addressed before new biomarker assays can be introduced into clinical trials are discussed.

Since the discovery of the CFTR gene mutations which cause cystic fibrosis (CF) in 1989 the average life expectancy of CF patients has almost doubled and now exceeds 37 years. The advances in molecular diagnostics and medical treatments expanded beyond the CF patient population as some of the newest treatments are also being tested for treatment of complex diseases such as COPD and other inherited disorders. Rapid development of CF therapeutics is important for the cystic fibrosis community and is an excellent example for other nonprofit organizations, disease foundations and pharmaceutical companies alike. Better understanding of disease variability and underlying molecular mechanisms through genetic association studies aimed to identify novel CF modifier genes opens new venues for targeted drug design. Furthermore, these genetic studies allow development of molecular diagnostic tests for patient population stratification and treatment personalization, which is already being done for CF patients with specific mutations in the CFTR gene, as well as implementation of new molecular tests for reliable assessment of disease progression and severity

The field of inhaled antibiotics that target Pseudomonas aeruginosa infections has made substantial contributions to the health, disease management, and life expectancies of individuals with cystic fibrosis (CF) over the last three decades [1-3]. This paper reviews some of the recent clinical developments in the field of inhaled antibiotics for CF and briefly describes formulations and ongoing developments for US and/or European regulatory approvals. Lung delivery technologies, in regards to inhaled antibiotics for CF, are also reviewed

The development of antimicrobial treatments for respiratory pathogens in cystic fibrosis (CF) has been an integral component to the increased survival of CF patients over the past fifty years. Despite significant treatment advances, however, respiratory failure secondary to chronic bacterial pulmonary infection remains the primary cause of death in CF patients. The purpose of this review is to discuss emerging pathogens (other than Pseudomonas) in CF by describing the characteristics of the organism, their clinical significance in CF, their mechanisms of antimicrobial resistance and the current treatment approaches including newer pharmaceutical modalities. This review will focus on the following pathogens: Burkholderia cepacia complex, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, methicillin-resistant Staphylococcus aureus and nontuberculous mycobacteria The goal is to familiarize the reader with the challenges in treating pulmonary infections in CF caused by multi-drug resistant pathogens and to highlight some of the newer pharmaceutical treatments that are currently the focus of intense research.

The concentrations of nitric oxide are decreased in airways of patients with cystic fibrosis. The reasons for this nitric oxide deficiency are incompletely understood but may include reduced production from nitric oxide synthases due to decreased expression, the enzymes in airway epithelial cells, reduced availability of L-arginine, the substrate for nitric oxide synthases, and the presence of endogenous inhibitors of the enzymes in the airways. As nitric oxide plays a role in a number of important physiological processes in the lung including host defense against pathogens such as Pseudomonas aeruginosa, inflammation and the regulation of vascular and broncho motor tone, the lack of nitric oxide may contribute to lung disease in cystic fibrosis patients. Therapeutic interventions aiming to correct the nitric oxide deficiency in the cystic fibrosis airways are therefore currently being explored as new therapies for these patients.

Lung transplantation has evolved as an accepted therapy in selected adults and children with end-stage lung disease. Outcomes following lung transplantation have improved in the recent era with a 5-year survival of >70% and an overall good functional status of surviving recipients. Many of the advances have been achieved by the use of modern immunosuppressive agents. To date, multiple strategies exist that may be employed when utilizing immunosuppression. These agents can be used in a variety of roles that may include induction, maintenance or rescue therapy, many of which are illustrated in this review including the current evidence to support their use. Infections in lung transplant recipients remain a significant cause of morbidity and mortality. Special considerations are required with the substantial burden of chronic infection in candidates with CF lung disease before transplantation, which are discussed. Furthermore, recent progress and advances in prevention and treatment of post-transplantation infectious complications are detailed. Chronic lung allograft dysfunction remains to be the burden of lung transplantation in the long-term. Unfortunately, there is no well-established therapy to address it. However, therapy attempts include change/augmentation of immunosupression, use of neomacrolides and extracorporeal photopheresis, all of which are reviewed in detail.