Novel pharmaceutical approaches for treating patients with cystic fibrosis

Before the cloning of the CFTR gene in 1989, there were relatively few treatment options for the many phenotypes associated with cystic fibrosis (CF). The advancement of research in areas such as immunology, molecular biology and pharmacology have provided new insights into the mechanism and evolution of CF. More than 40 systematic clinical trials evaluating new therapies for CF are presently registered with the NIH. A great deal of effort is focused on the main cause of mortality: chronic and persistent lung infections. Intestinal malabsorption, pancreatic insufficiency, reduced bone mineral density and reproductive abnormalities are other manifestations of this disease that have been targeted by innovated treatments which are giving renewed hope to CF patients and their families. The following review is a summary of the novel pharmaceutical approaches for the treatment of cystic fibrosis aimed at improving both the quality and the longevity of the lives of patients afflicted with this devastating disease.     

Emerging drugs for cystic fibrosis

Introduction: Cystic fibrosis is an autosomal recessive disease, which is the result of a genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Pulmonary disease accounts for over 90% of the morbidity and mortality associated with the disease. Conventionally, CF treatment has focused on symptomatic therapy.

Areas covered: In the past, the emphasis for the development of CF therapeutics has previously been on addressing complications of the manifestations rather than on the underlying disease process. However, in the past few decades there has been a paradigm shift with new attention on the underlying biological mechanisms and therapies targeted at curing the disease rather than simply controlling it. This review summarizes the current CF therapeutics pipeline. These developing therapies include CFTR gene therapy, CFTR pharmacotherapeutics, osmotically active agents and anti-inflammatory therapies, as well as novel inhaled antibiotics.

Expert opinion: The CF therapeutics pipeline currently holds great promise both for novel therapies directly targeting the underlying biological mechanisms of CFTR dysfunction and new symptomatic therapies. While CFTR-directed therapy has the highest potential to improve patients' outcome, it is important to continue to develop better treatment options for all aspects of CF lung disease.     

Modifier gene studies to identify new therapeutic targets in cystic fibrosis

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.     

Toward the pharmacogenomics of cystic fibrosis--an update

Cystic fibrosis (CF) is the most common autosomal recessive disorder in Caucasians, with a frequency of approximately 1 in 3000 live births. The mutated gene is a defective chloride channel in epithelial cells, named cystic fibrosis transmembrane conductance regulator (CFTR). Several different protocols for the scanning of the entire gene have aided molecular diagnosis and improved our understanding of the disorder's pathophysiology, but also showed the disease's complexity. Therefore, CF phenotype remains difficult to predict from CFTR mutation data alone: several studies have suggested that additional genes could modulate its clinical outcome. Gene replacement therapy is still far from being used in patients with CF, mostly due to the difficulties with targeting the appropriate cells. In this review, we summarize recent advances, both in the pharmacological and gene therapy field, aimed for the treatment of the disease.     

The changing landscape of the cystic fibrosis lung environment: From the perspective of Pseudomonas aeruginosa

This review guides the reader through the current understanding of the dynamic changes that occur within the cystic fibrosis (CF) lung that allow Pseudomonas aeruginosa to become the dominant pathogen associated with CF. Although recent studies provide some insight, the mechanisms that drive the changing landscape of the lung environment throughout an individual’s lifetime that prime P. aeruginosa to take over and establish chronic infection within the lungs, remain poorly understood. We explore how the CF lung environment shapes the ability of P. aeruginosa to persist in spite of intense antimicrobial therapy. We also highlight the pioneering use of a triple combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, Trikafta, to restore CFTR function and how it influences P. aeruginosa persistence in the CF lung. We utilize existing data for single modulator therapies to extrapolate the potential future of pathogen infection in the era of Trikafta therapy.     

Mucus-targeting therapies of defective mucus clearance for cystic fibrosis: A short review

In the lungs, defective CFTR associated with cystic fibrosis (CF) represents the nidus for abnormal mucus clearance in the airways and consequently a progressive lung disease. Defective CFTR-mediated Cl⁻ secretion results in altered mucus properties, including concentration, viscoelasticity, and the ratio of the two mucins, MUC5B and MUC5AC. In the past decades, therapies targeting the CF mucus defect, directly or indirectly, have been developed; nevertheless, better treatments to prevent the disease progression are still needed. This review summarizes the existing knowledge on the defective mucus in CF disease and highlights it as a barrier to the development of future inhaled genetic therapies. The use of new mucus-targeting treatments is also discussed, focusing on their potential role to halt the progress of CF lung disease.     

Cystic fibrosis: can epithelial function be restored?

The treatment of cystic fibrosis (CF) is still very much concerned with alleviating its symptoms. However, despite the considerable increase in the knowledge of the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, no magic bullet for the treatment of CF is in sight. This review focuses on what is known about the ion transport defect and which pharmacological and molecular approaches have the greatest potential to provide a cure in the future.     

Nano-based theranostics for chronic obstructive lung diseases: challenges and therapeutic potential

The major challenges in the delivery and therapeutic efficacy of nano-delivery systems in chronic obstructive airway conditions are airway defense, severe inflammation and mucous hypersecretion. Chronic airway inflammation and mucous hypersecretion are hallmarks of chronic obstructive airway diseases, including asthma, COPD (chronic obstructive pulmonary disease) and CF (cystic fibrosis). Distinct etiologies drive inflammation and mucous hypersecretion in these diseases, which are further induced by infection or components of cigarette smoke. Controlling chronic inflammation is at the root of treatments such as corticosteroids, antibiotics or other available drugs, which pose the challenge of sustained delivery of drugs to target cells or tissues. In spite of the wide application of nano-based drug delivery systems, very few are tested to date. Targeted nanoparticle-mediated sustained drug delivery is required to control inflammatory cell chemotaxis, fibrosis, protease-mediated chronic emphysema and/or chronic lung obstruction in COPD. Moreover, targeted epithelial delivery is indispensable for correcting the underlying defects in CF and targeted inflammatory cell delivery for controlling other chronic inflammatory lung diseases. We propose that the design and development of nano-based targeted theranostic vehicles with therapeutic, imaging and airway-defense penetrating capability, will be invaluable for treating chronic obstructive lung diseases. This paper discusses a novel nano-theranostic strategy that we are currently evaluating to treat the underlying cause of CF and COPD lung disease.     

Tobramycin solution for inhalation in cystic fibrosis patients: a review of the literature

Cystic fibrosis patients suffer increased sputum production and a notable decline in respiratory function throughout the progression of their disease. Patients are left vulnerable to respiratory colonization/infection from a number of pathogens, including Pseudomonas aeruginosa. At present, the only antibiotic formulation that is FDA approved for aerosolized delivery is tobramycin solution for inhalation (TSI). TSI allows for targeted antibiotic delivery to the lungs and is indicated for maintenance therapy in cystic fibrosis patients infected with P. aeruginosa. Studies demonstrate that cyclical treatment with TSI is associated with an increase in respiratory function and a decrease in sputum density in cystic fibrosis patients. Additional benefits include fewer hospitalizations and a decreased need for systemic antibiotics. However, because of the need for chronic administration, issues such as emergence of resistant organisms and toxicity are a potential concern and have also been evaluated. This review details the pharmacology of TSI and literature involving its use in cystic fibrosis patients.     

Nano-based theranostics for chronic obstructive lung diseases: challenges and therapeutic potential

The major challenges in the delivery and therapeutic efficacy of nano-delivery systems in chronic obstructive airway conditions are airway defense, severe inflammation and mucous hypersecretion. Chronic airway inflammation and mucous hypersecretion are hallmarks of chronic obstructive airway diseases, including asthma, COPD (chronic obstructive pulmonary disease) and CF (cystic fibrosis). Distinct etiologies drive inflammation and mucous hypersecretion in these diseases, which are further induced by infection or components of cigarette smoke. Controlling chronic inflammation is at the root of treatments such as corticosteroids, antibiotics or other available drugs, which pose the challenge of sustained delivery of drugs to target cells or tissues. In spite of the wide application of nano-based drug delivery systems, very few are tested to date. Targeted nanoparticle-mediated sustained drug delivery is required to control inflammatory cell chemotaxis, fibrosis, protease-mediated chronic emphysema and/or chronic lung obstruction in COPD. Moreover, targeted epithelial delivery is indispensable for correcting the underlying defects in CF and targeted inflammatory cell delivery for controlling other chronic inflammatory lung diseases. We propose that the design and development of nano-based targeted theranostic vehicles with therapeutic, imaging and airway-defense penetrating capability, will be invaluable for treating chronic obstructive lung diseases. This paper discusses a novel nano-theranostic strategy that we are currently evaluating to treat the underlying cause of CF and COPD lung disease.     

New perspectives and hope for cure-reflecting recent genetic developments in cystic fibrosis.

The isolation of cystic fibrosis gene at the CF locus assigned to the long arm of chromosome 7 band q31 and definition of its protein product named CFTR (cystic fibrosis transmembrane conductance regulator) permits to understand the basic defect in this inherited disorder known as cystic fibrosis (CF) or mucoviscidosis. A variety of mutations of CF gene was revealed and the most common, a deletion of the 3 nucleotides that encode phenylalanine (Delta F508) with the variable incidence among the different ethnic groups of CF patients was delineated. CF is a variable disease and genetic testing can be useful to explain this variation but to date the phenotype-genotype correlation is not clarified. Polymerase chain reaction (PCR) amplification is used to test CF gene in CF patients and their families but is not sufficiently genetically informative to population screening for carrier detections. Recently identified glycoprotein encoded by CF gene is responsible for the regulation of the membrane chloride channel of epithelial cells and the experiments used retro-virus-mediated gene transfer demonstrated complementation CF defect in vitro. The way for gene therapy in this disease is open. An alternative approach to use the germ line cells to CF gene therapy is prerequisite of the development of the preimplantation preconception genetic CF diagnosis. The researchers managed already to express human CFTR gene in vivo in cotton rats lungs through the viral delivery system. It will be generalized into the airways of CF patients with hope that normal CFTR will reverse the physiological defect in CF cells.     

New treatments for emerging cystic fibrosis pathogens other than Pseudomonas

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.     

Targeting airway inflammation in cystic fibrosis in children: past, present, and future

Inflammation is a major component of the vicious cycle characterizing cystic fibrosis (CF) pulmonary disease. If untreated, this inflammatory process irreversibly damages the airways, leading to bronchiectasis and ultimately respiratory failure. Anti-inflammatory drugs for CF lung disease appear to have beneficial effects on disease progression. These agents include oral corticosteroids and ibuprofen, as well as azithromycin, which, in addition to its antimicrobial effects, also possess anti-inflammatory properties. Inhaled corticosteroids, antioxidants, nutritional supplements, and protease inhibitors have a limited impact on the disease. Adverse effects limit therapy with oral corticosteroids and ibuprofen. Azithromycin appears to be safe and effective, and is thus the most promising anti-inflammatory therapy available for patients with CF. Pharmacologic therapy with anti-inflammatory agents should be started early in the disease course, before extensive irreversible lung damage has occurred. To optimize anti-inflammatory therapy, it is necessary to understand the mechanism of action of these agents in the CF lung, to determine which of these agents would provide the most benefit to patients with CF, and to determine which therapies should be initiated at what age or stage of lung disease.     

CFTR RNA- and DNA-based therapies

This review provides an update on recent developments of RNA- and DNA-based methodologies and their intracellular targets in the context of cystic fibrosis (CF) lung disease. Ultimately, clinical success will require a suitable delivery system, but since the cargo for all these strategies is nucleic acid, it should hopefully be possible to exploit delivery breakthroughs from one study and apply these innovations to other experiments in order to identify the best strategy for everyone with CF. Ultimately, it may be the same approach for everyone, or possibly a number of different strategies tailored to particular mutations or classes/groups of mutations. And whilst the current focus is on CF lung disease, in the longer term the goal is to treat all affected organs in people with CF such as the pancreas, gut, and liver.     

Nanotechnology approaches for inhalation treatment of fibrosis

Abstract

Cystic fibrosis (CF) is an autosomal recessive monogenetic disease that afflicts nearly 70?000 patients worldwide. The mutation results in the accumulation of viscous mucus in multiple organs especially in the lungs, liver and pancreas. High associated morbidity and mortality is caused by CF due to the lack of effective therapies. It is widely accepted that morbidity and mortality caused by CF is primarily due to the respiratory manifestations of the disease. Consequently, several approaches were recently developed for treatment of lung complications of CF. However, the lack of effective methods for delivery and especially targeted delivery of therapeutics specifically to lung tissues and cells limits the efficiency of the therapy. Local pulmonary delivery of therapeutics has two major advantages over systemic application. First, it enhances the accumulation of therapeutics specifically in the lungs and therefore increases the efficiency of the treatment. Second, local lung delivery substantially prevents the penetration of the delivered drug into the systemic circulation limiting adverse side effects of the treatment on other organs and tissues. This review is focused on different approaches to the treatment of respiratory manifestations of CF as well as on methods of pulmonary delivery of therapeutics.     

Gene therapy for cystic fibrosis by means of aerosol.

Gene therapy by aerosol is an attractive approach for the treatment of cystic fibrosis (CF). Clinical trials with aerosols in CF patients have been conducted by five different groups, three using adenoviral vectors and two using cationic liposomes carrying the coding sequence for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). These trials revealed that gene transfer from the lumen to the respiratory epithelium can currently be achieved in vivo, but only with low efficiency and for limited duration. Some of the many hurdles on the way to successful gene therapy for this disease will be discussed in this review. Innovative strategies need to be developed to reach this tantalizing goal.     

Metabolomics of airways disease in cystic fibrosis

While discovery metabolomic studies have identified many potential biomarkers of cystic fibrosis (CF) airways disease, relatively few have been validated. We review the recent literature to identify the most promising metabolomic findings as those repeatedly observed over multiple studies. Reproducible metabolomic findings include increased airway amino acids and small peptides in CF airways, as well as changes in phospholipids and sphingolipids. Other commonly altered pathways include adenosine metabolism, polyamine synthesis, and oxidative stress. These pathways represent potential biomarkers and therapeutic targets, though findings require reevaluation in the era of highly effective modulator therapies. Analysis of airway biomarkers in exhaled breath holds promise for non-invasive detection, though technical challenges will need to be overcome.     

The molecular mechanisms of glucocorticoids-mediated neutrophil survival

Neutrophil-dominated inflammation plays an important role in many airway diseases including asthma, chronic obstructive pulmonary disease (COPD), bronchiolitis and cystic fibrosis. In cases of asthma where neutrophil-dominated inflammation is a major contributing factor to the disease, treatment with corticosteroids can be problematic as corticosteroids have been shown to promote neutrophil survival which, in turn, accentuates neutrophilic inflammation. In light of such cases, novel targeted medications must be developed that could control neutrophilic inflammation while still maintaining their antibacterial/anti-fungal properties, thus allowing individuals to maintain effective innate immune responses to invading pathogens. The aim of this review is to describe the molecular mechanisms of neutrophil apoptosis and how these pathways are modulated by glucocorticoids. These new findings are of potential clinical value and provide further insight into treatment of neutrophilic inflammation in lung disease.     

Animal models of cystic fibrosis in the era of highly effective modulator therapies

Few human genetic diseases can rely on the availability of as many and as diverse animal models as cystic fibrosis (CF), a multiorgan syndrome caused by functional absence of cystic fibrosis transmembrane regulator (CFTR). The recent development of highly effective CFTR modulator drug therapies simultaneously highlighted the remarkable clinical improvement achievable with these treatments, the lack of therapeutic alternatives for non-responders, and the need to understand the kinetics of disease upon early life/chronic treatment. These advances have rekindled efforts to leverage animal models to address critical knowledge gaps in CF. This article provides a concise overview of the areas of interests for therapeutic intervention in the current CF landscape, focusing on the contributions of in vivo models to understand CF pathogenesis, identify therapeutic windows, and develop novel therapies for all CFTR mutations.