Cystic Fibrosis Transmembrane Regulator Modulators Research Articles

Female reproductive health in cystic fibrosis

Women with cystic fibrosis (CF) are living longer and healthier lives, and opportunities for childbearing are increasingly promising. However, this population can also face sexual and reproductive health concerns, including menstrual irregularities, unplanned pregnancies, infertility and pregnancy complications. Additionally, more women are entering menopause and are at risk for the consequences of estrogen deficiency. The exact mechanisms involved in female reproductive health conditions in CF are not clearly understood, but are thought to include cystic fibrosis transmembrane regulator (CFTR)-mediated abnormalities, changes in female sex hormones, and other CF health-related factors. In the era of CFTR modulator therapy, new data are necessary to understand the impact of CFTR modulation on contraceptive effectiveness, fertility, and pregnancy outcomes to help guide future clinical care. This article reviews the current scientific knowledge of major reproductive health issues for women with CF.

Validity and Reliability of a Novel Multimodal Questionnaire for the Assessment of Abdominal Symptoms in People with Cystic Fibrosis (CFAbd-Score).

For people with cystic fibrosis, validated patient-reported outcome measures for the assessment of the complex abdominal involvement are lacking. The objective of this study was to examine whether the CFAbd-Score, a novel questionnaire consisting of 28 items, meets the essential requirements (validity and reliability) for a patient-reported outcome measure according to US Food and Drug Administration recommendations. Content validity was assessed by recording the frequencies and severity of symptoms that occurred during the prior 2weeks in patients with cystic fibrosis (n = 116; aged ≥ 6years). Comparing the CFAbd-Score results obtained from patients with cystic fibrosis and healthy controls (n = 88), we determined known-groups validity. To explore the structure of the patient-reported outcome measure, a factor analysis was conducted. Internal consistency of the five extracted score domains was assessed using Cronbach's alpha. For test-retest reliability, a subgroup of patients (n = 43) was reevaluated and intra-class correlation coefficients were determined. The CFAbd-Score differentiated patients with cystic fibrosis from healthy controls with a large effect size (17.3 ± 1.1 vs. 8.0 ± 0.7 points; p < 0.001; Cohen's d = 0.85). Items, domains, and scores reflected the relevance to patients with cystic fibrosis and allowed a differentiation between subgroups of patients with cystic fibrosis (e.g., patients with and without abdominal pain, pancreatic sufficiency, and age groups). High item-domain loadings as well as good to excellent internal consistency and reproducibility (Cronbach's α = 0.70-0.92; intra-class correlation coefficient = 0.932, 95% confidence interval 0.874-0.963) indicated construct validity and reliability. The CFAbd-Score has successfully passed through key steps of the iterative process of patient-reported outcome measure development. Prospectively, the CFAbd-Score is proposed as a patient-centered instrument for monitoring abdominal symptoms and, most interestingly, for evaluating changes in symptoms with novel treatments such as cystic fibrosis transmembrane regulator modulators. ClinicalTrials.gov: NCT03052283.

Cystic fibrosis - an example of personalized and precision medicine.

Cystic fibrosis (CF) is a severe, monogenic, autosomal recessive disease caused by mutations in the CFTR (cystic fibrosis transmembrane regulator) gene, where disturbed chloride and bicarbonate transportation in epithelial cells results in a multiorgan disease with primarily pulmonary infections and pancreatic insufficiency. In 1968, the Copenhagen CF Center was established, and centralized care of CF patients with monthly control was introduced. Close monitoring and treatment of Pseudomonas lung infection as well as segregation of patients with different infection status improved the clinical outcome as well as survival. Prophylactic basic treatment as well as infection treatments follow specific algorithms. A variety of comorbidities have all along the pulmonary infection control necessitated personalized care, adjusted to the patients' phenotype. With the introduction of CFTR modulators, the treatment has shifted from prophylactic, symptomatic type toward a new era of precision medicine targeting the basic defect according to the patients' CFTR genotype. Future directions will focus on further improvement of the CFTR modulators and gene therapy, as well as modifier genes and CF phenotype.

The combination of tezacaftor and ivacaftor in the treatment of patients with cystic fibrosis: clinical evidence and future prospects in cystic fibrosis therapy.

Years of tremendous study have dawned a new era for the treatment of cystic fibrosis (CF). For years CF care was rooted in the management of organ dysfunction resulting from the mal-effects of absent anion transport through the CF transmembrane regulator (CFTR) protein. CFTR, an adenosine triphosphate binding anion channel, has multiple functions, but primarily regulates the movement of chloride anions, thiocyanate and bicarbonate across luminal cell membranes. Additional roles include effects on other electrolyte channels such as the epithelial sodium channel (ENaC) and on pulmonary innate immunity.Inappropriate luminal anion movement leads to elevated sweat chloride concentrations, dehydrated airway surface liquid, overall viscous mucous production, and inspissated bile and pancreatic secretions. As a result, patients develop the well-known CF symptoms and disease-defining complications such as chronic cough, oily stools, recurrent pulmonary infections, bronchiectasis, chronic sinusitis and malnutrition.Traditionally, CF has been symptomatically managed, but over the past 6 years those with CF have been offered a new mode of therapy; CFTR protein modulation. These medications affect the basic defect in CF: abnormal CFTR function. Ivacaftor, approved for use in the United States in 2012, is the first medication in CF history to improve CFTR function at the molecular level. Its study and approval were followed by two additional CFTR modulators, lumacaftor/ivacaftor and tezacaftor/ivacaftor.To effectively use currently available CF therapies, clinicians should be familiar with the side effects of the drugs and their impacts on patient outcomes. As many new modulators are on the horizon, this information will equip providers to discuss the benefits and shortcomings of modulator therapy especially in the context of limited healthcare resources.

Effect of ivacaftor on mucociliary clearance and clinical outcomes in cystic fibrosis patients with G551D-CFTR.

The ability to restore cystic fibrosis transmembrane regulator (CFTR) function with effective small molecule modulators in patients with cystic fibrosis provides an opportunity to study relationships between CFTR ion channel function, organ level physiology, and clinical outcomes. We performed a multisite, prospective, observational study of ivacaftor, prescribed in patients with the G551D-CFTR mutation. Measurements of lung mucociliary clearance (MCC) were performed before and after treatment initiation (1 and 3 months), in parallel with clinical outcome measures. Marked acceleration in whole lung, central lung, and peripheral lung MCC was observed 1 month after beginning ivacaftor and was sustained at 3 months. Improvements in MCC correlated with improvements in forced expiratory volume in the first second (FEV1) but not sweat chloride or symptom scores. Restoration of CFTR activity with ivacaftor led to significant improvements in MCC. This physiologic assessment provides a means to characterize future CFTR modulator therapies and may help to predict improvements in lung function. ClinicialTrials.gov, NCT01521338. CFF Therapeutics (GOAL11K1).

Development of rAAV2-CFTR: History of the First rAAV Vector Product to be Used in Humans.

The first human gene therapy trials using recombinant adeno-associated virus (rAAV) vectors were performed in cystic fibrosis (CF) patients. Over 100 CF patients were enrolled in 5 separate trials of rAAV2-CFTR administration via nasal, endobronchial, maxillary sinus, and aerosol delivery. Recombinant AAV vectors were designed to deliver the CF transmembrane regulator (CFTR) gene and correct the basic CFTR defect by restoring chloride transport and reverting the upregulation of proinflammatory cytokines. However, vector DNA expression was limited in duration because of the low incidence of integration and natural airway epithelium turnover. In addition, repeated administration of AAV-CFTR vector resulted in a humoral immune response that prevented effective gene transfer from subsequent doses of vector. AAV serotype 2 was used in human trials before the comparison with other serotypes and determination that serotypes 1 and 5 not only possess higher tropism for the airway epithelium, but also are capable of bypassing the binding and trafficking processes-both were important hindrances to the effectiveness of rAAV2. Although rAAV-CFTR gene therapy does not appear likely to supplant newer small-molecule CFTR modulators in the near future, early work with rAAV-CFTR provided an important foundation for later use of rAAV in humans.

Cystic Fibrosis: A Novel Pharmacologic Approach to Cystic Fibrosis Transmembrane Regulator Modulation Therapy.

Therapy for cystic fibrosis (CF) has progressed during the past several decades. Much of this progress is because of advances in genetic testing to precisely identify the underlying cause of CF transmembrane regulator (CFTR) dysfunction. However, with more than 1900 mutations that can produce a faulty CFTR, the management of CF can remain a challenge. Several innovative drugs recently approved by the Food and Drug Administration, termed genetic modulators, target the underlying disease by modulating the CFTR defect. This review provides physicians with an established simple classification scheme to guide their use of these drugs. The treatment challenge of 1900 CFTR mutations has been simplified into 6 physiologic classes, each paired with an available therapy to offer patients the most functional improvement. Drug therapy monitoring, adverse effects, and indications for discontinuation must also be considered.

Novel picolinamide-based cystic fibrosis transmembrane regulator modulators: evaluation of WO2013038373, WO2013038376, WO2013038381, WO2013038386 and WO2013038390

Cystic fibrosis (CF) is a genetic disease caused by defects in the CF transmembrane regulator (CFTR) gene, which encodes an epithelial chloride channel. The most common mutation, Δ508CFTR, produces a protein that is misfolded and does not reach the cell membrane. The discovery that partial chloride channel function could be restored by exposure to exogenous chemical stimuli led to the search for selective CFTR modulators. Vertex has led the way in developing N-aryl-1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide derivatives such as lumacaftor and VX-661, which correct trafficking of Δ508CFTR and partially restore chloride channel activity. Novartis had identified similar activity in a series of picolinamide derivatives such as 3-amino-N-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5,6-bis(trifluoromethyl)pyridine-2-carboxamide. A series of five filings from Novartis has expanded on the activity of compounds based on this scaffold and provided compounds with nanomolar potency in cellular assays.