Cystic fibrosis is a complex disease entity that presents considerable lifelong challenges. Implementation of medical and surgical treatment options involves multisystem interventions to prevent and treat lung and gastrointestinal manifestations of cystic fibrosis and associated comorbidities. From birth through adulthood, cystic fibrosis care entails a longitudinal regimen aimed at achieving relief of disease symptoms and enhanced life expectancy. With increased knowledge of the molecular behavior of the cystic fibrosis transmembrane conductance regulator (CFTR) in health and disease, clinical practice has been enriched by the prospect of novel strategies, including mutation-specific drug and gene therapy targeting restoration of corrupted transepithelial ion transport. Emerging paradigms of comprehensive care increasingly enable personalized solutions to address the root cause of disease-transforming management options for individuals with cystic fibrosis.Clinical Pharmacology & Therapeutics (2012); advance online publication 14 November 2012. doi:10.1038/clpt.2012.183.
"Cystic fibrosis (CF), one of the most severe genetic diseases with recessive inheritance among people of Caucasian origin, is caused by mutations in the gene coding for Cystic Fibrosis Conductance Transmembrane Regulator (CFTR)  . CFTR mutations impact cell types and the corresponding tissues differently, with various lung and gastrointestinal manifestations of CF and associated comorbidities among affected patients . Although earlier pathogenic models proposed most of the pulmonary complications of CF to be a direct consequence of epithelial dysfunctions caused by the absence of functional CFTR, more recent clinical and experimental observations have suggested that a defective CFTR alters the function of cells of the immune system slowing the resolution of inflammation and infection  . "
[Show abstract][Hide abstract] ABSTRACT: Background: Cystic fibrosis is caused by mutations of CFTR gene, a protein kinase A-activated anion channel, and is associated to a persistent and excessive chronic lung inflammation, suggesting functional alterations of immune cells. Leukocytes express detectable levels of CFTR but the molecule has not been fully characterized in these cells. Methods: Freshly isolated monocytes from healthy individuals and CF patients were assessed by protein expression, single cell electrophysiological and membrane depolarization assays. Results: We recorded chloride currents by patch clamp in healthy monocytes, after the administration of a CFTR stimulus. Currents were sensitive to a specific blocker of the CFTR channel, CFTRinh-172 and were absent in CF monocytes. Next, we evaluated the effects of ex vivo exposure of monocytes from cystic fibrosis patients carrying the F508del mutation to a chemical corrector, Vertex-325. We found an increase in CFTR expression by confocal microscopy and a recovery of CFTR function by both patch clamp and single cell fluorescence analysis. Conclusions: We confirm the expression of functional CFTR in human monocytes and demonstrate that blood monocytes can represent an adequate source of primary cells to assess new therapies and define diagnosis of CF. General significance: Tests to evaluate CFTR functional abnormalities in CF disease might greatly benefit from the availability of a convenient source of primary cells. This electrophysiological study promotes the use of monocytes as a minimally invasive tool to study and monitor CFTR function in individual patients.
Biochimica et Biophysica Acta (BBA) - General Subjects 07/2014; 1840(10). DOI:10.1016/j.bbagen.2014.07.010 · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Enabling science and information technologies has catalyzed a surge of biological, clinical, demographic, health services, and comparative-effectiveness data. While accelerating the deconvolution of complex pathophysiological, medical, social, and environmental networks and systems, these platforms have produced informational quanta devoid of contextualization. Therapeutic innovation is thus now challenged with moving beyond knowledge generation and curation to integrated solution-seeking paradigms that organize functionally related information, producing system-level insights into health and disease for optimized patient-centered outcomes. This annual issue on therapeutics innovations highlights emerging considerations for the generation and hierarchical organization of scientific and clinical information and its translation to advancing next-generation disease management.
[Show abstract][Hide abstract] ABSTRACT: Cystic fibrosis (CF), the most common, life-threatening monogenetic disease in Caucasians, is caused by mutations in the CFTR gene, encoding a cAMP-and cGMP-regulated epithelial chloride channel. Symptomatic therapies treating end-organ manifestations have increased the life expectancy of CF patients towards a mean of 40 years. The recent development of CFTR-targeted drugs that emerged from high throughput screening and are capable of correcting the basic defect promises to transform the therapeutic landscape from a trial-and-error prescription to personalized medicine. This stratified approach is tailored to a specific functional class of mutations in CFTR, but can be refined further to an individual level by exploiting recent advances in ex vivo drug testing methods. These tests range from CFTR functional measurements in rectal biopsies donated by a CF patient to the use of patient-derived intestinal or pulmonary organoids. Such organoids may serve as an inexhaustible source of epithelial cells that can be stored in biobanks and allow medium- to high-throughput screening of CFTR activators, correctors and potentiators on the basis of a simple microscopic assay monitoring organoid swelling. Thus the recent breakthrough in stem cell biology allowing the culturing of mini-organs from individual patients is not only relevant for future stem cell therapy, but may also allow the preclinical testing of new drugs or combinations that are optimally suited for an individual patient.
The international journal of biochemistry & cell biology 07/2014; 52. DOI:10.1016/j.biocel.2014.02.008 · 4.05 Impact Factor
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