Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations. We observed that CFTR residual function and responses to drug therapy depended on both the CFTR mutation and the genetic background of the subjects. In vitro drug responses in rectal organoids positively correlated with published outcome data from clinical trials with VX-809 and VX-770, allowing us to predict from preclinical data the potential for CF patients carrying rare CFTR mutations to respond to drug therapy. We demonstrated proof of principle by selecting two subjects expressing an uncharacterized rare CFTR genotype (G1249R/F508del) who showed clinical responses to treatment with ivacaftor and one subject (F508del/R347P) who showed a limited response to drug therapy both in vitro and in vivo. These data suggest that in vitro measurements of CFTR function in patient-derived rectal organoids may be useful for identifying subjects who would benefit from CFTR-correcting treatment, independent of their CFTR mutation.
Highlights d Organoids of CF patients were used to quantitate individual drug response in vitro d Organoid responses correlate with two clinical response parameters ppFEV 1 and SCC d In vivo (non)responders were identified with a PPV of 100% and a NPV of 80%
Asthma is a chronic airway disease characterized by paroxysmal airflow obstruction evoked by irritative stimuli on a background of allergic lung inflammation. Currently, there is no cure for asthma, only symptomatic treatment. In recent years, our understanding of the involvement of coagulation and anticoagulant pathways, the fibrinolytic system, and platelets in the pathophysiology of asthma has increased considerably. Asthma is associated with a procoagulant state in the bronchoalveolar space, further aggravated by impaired local activities of the anticoagulant protein C system and fibrinolysis. Protease-activated receptors have been implicated as the molecular link between coagulation and allergic inflammation in asthma. This review summarizes current knowledge of the impact of the disturbed hemostatic balance in the lungs on asthma severity and manifestations and identifies new possible targets for asthma treatment. (Blood. 2012;119(14):3236-3244) IntroductionAsthma is a disease of chronic airway inflammation causing symptoms of paroxysmal airflow obstruction, airway hyperresponsiveness to irritative stimuli, wheezing, chest tightness, and coughing. 1 These symptoms occur against a background of allergic inflammation, characterized by infiltration of mast cells, eosinophils, and T-helper 2 (Th2) lymphocytes into the airway wall and mucus hypersecretion. Many patients with chronic asthma show progressive decline of lung function that is thought to be the result of structural remodeling of the airway wall 2 and have frequent exacerbations and steroid resistance, 3 posing a major clinical challenge and health problem. 4 New therapeutic approaches need to be developed targeting the inflammatory background that triggers asthma symptoms. 5 Historically, coagulation and fibrinolysis have been considered as processes that take place in the vascular compartment. It is now appreciated that the airways represent a body compartment in which coagulation and anticoagulant mechanisms can be initiated and regulated locally. 6 In addition to the activation of coagulation in lung inflammatory disorders that is probably induced by leakage of plasma proteins into the bronchoalveolar space, essential mediators of coagulation can be found locally in the lung, including tissue factor (TF) that initiates coagulation and thrombin, which transforms fibrinogen to fibrin. 7 Several diseases associated with abundant lung inflammation, including acute respiratory distress syndrome, pneumonia, and lung fibrosis, 6,8 have been shown to result in similar changes in bronchoalveolar levels of proteins implicated in coagulation and fibrinolysis, tipping the physiologic equilibrium of preventing fibrin clot formation toward a net procoagulant state. In particular, for asthma this disturbed hemostatic balance in the airways is of importance for the perpetuation of allergic inflammation (Figure 1) in which cytokines and protease-activated receptors (PARs) play an important role. In addition, platelets have been found to actively participate in ma...
Increasing evidence suggests that patients with asthma have activated coagulation within the airways. Whether this leads to an increase in venous thromboembolic events is unknown. We therefore assessed the incidence of venous thromboembolic events in patients with mild-to-moderate and severe asthma as compared with an age-and sex-matched reference population.648 patients with asthma (283 with severe and 365 patients with mild-to-moderate asthma) visiting three Dutch outpatient asthma clinics were studied. All patients completed a questionnaire about a diagnosis of deep vein thrombosis and pulmonary embolism in the past, their risk factors, history of asthma and medication use. All venous thromboembolic events were objectively verified.In total, 35 venous thromboembolic events (16 deep vein thrombosis and 19 pulmonary embolism) occurred at a median age of 39 (range 20-63) years. The incidence of pulmonary embolism in patients with severe asthma was 0.93 (95% CI 0.42-1.44) per 1000 person-years, 0.33 (95% CI 0.07-0.60) in mild-tomoderate asthma and 0.18 (95% CI 0.03-0.33) in the general population, respectively. Severe asthma and oral corticosteroid use were independent risk factors of pulmonary embolism (hazard ratios 3.33 (1.16-9.93) and 2.82 (1.09-7.30), respectively). Asthma was not associated with deep vein thrombosis.Severe asthma greatly enhances the risk of pulmonary embolism, particularly if chronic corticosteroids are used. @ERSpublications Severe asthma greatly enhances the risk of pulmonary embolism, particularly if chronic corticosteroids are used
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