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PubMed1995

Identification of six novel CFTR mutations in a sample of Italian cystic fibrosis patients.

The spectrum of cystic fibrosis (CF) mutations has been determined in many populations of different ethnic and geographic origins. However, in the south of Europe, the commonest mutation, delta F508, accounts for only about 50% of CF chromosomes, while identification of most of the other mutant alleles has not been achieved. In an ongoing effort to identify these alleles, we have scanned the entire coding sequences of the CF gene using a GC clamp denaturing gradient gel electrophoresis assay in a sample of 57 chromosomes from patients of italian origin. We have identified six novel mutations (C276X, H139R, R117L, S42F, A1006E and 3121-2A---> T). Each has only been found once in this sample of CF patients.

Alleles↗

PubMed1988

Influence of the glomerular filtration rate on renal clearance of ceftazidime in cystic fibrosis.

The renal handling of ceftazidime was studied in 8 patients with cystic fibrosis and 10 healthy controls. The renal clearance of ceftazidime (CLRcz) was measured after an intravenous single dose and during low and high plasma concentration steady-state infusions. The glomerular filtration rate (GFR) was simultaneously estimated by inulin clearance (CL inul). The average CLRcz (mean +/- SD) was higher in cystic fibrosis patients (125 +/- 20 ml/min/1.73 m2) than in healthy controls (100 +/- 9 ml/min/1.73 m2) [p less than 0.005]. Also CL inul (mean +/- SD) was increased in cystic fibrosis patients (132 +/- 30 ml/min/1.73 m2) compared with healthy controls (103 +/- 8 ml/min/1.73 m2) [p less than 0.02]. The mean renal clearance ratios of ceftazidime to inulin were close to unity after both the single dose and low and high dose steady-state infusions both in cystic fibrosis patients and in controls. These findings suggest that the glomerular filtration rate is the principal determinant of the elimination rate of ceftazidime. However, in all cystic fibrosis patients with a CL inul exceeding 125 ml/min/1.73 m2 the clearance ratio was below unity, indicating tubular reabsorption of ceftazidime occurs in these individuals. The results demonstrate a higher but also more variable GFR in cystic fibrosis patients (74 to 174 ml/min/1.73 m2), resulting in increased and accordingly variable ability to eliminate ceftazidime in cystic fibrosis. However, these pharmacokinetic changes are not large enough to call for special dosage considerations for ceftazidime in cystic fibrosis.

Adolescent↗

PubMed1997

[Prenatal molecular diagnosis of cystic fibrosis. Report of 3 cases].

Cystic Fibrosis (CF) is a severe and relatively common autosomic recessive disease caused by a variety of mutations in the CFTR gene. The most frequent mutation worldwide, consists of the deletion of the phenylalanine codon at position 508 (delta F508). Here we report the first cases of prenatal diagnosis of CF by DNA analysis in couples at risk in Venezuela. The study focused on the detection of delta F508 alleles analyzing DNA recovered directly from amniocytes or from their cultures, using the polymerase chain reaction (PCR) and polyacrylamide gel electrophoresis. Two of three fetuses resulted homozygotic for the delta F508 allele and the third one turned out to be a delta F508 carrier. This information sustained the genetic counseling of the couples and allowed them to take objective reproductive decisions, a direct consequence of the availability of gene analysis at the DNA level.

Adult↗

PubMed1994

Amino acid residues lining the chloride channel of the cystic fibrosis transmembrane conductance regulator.

The cystic fibrosis transmembrane conductance regulator forms a chloride channel that is regulated by phosphorylation and intracellular ATP levels. The structure of the channel-forming domains is undetermined. To identify the residues lining this channel we substituted cysteine, one at a time, for 9 consecutive residues (91-99) in the M1 membrane-spanning segment. The cysteine substitution mutants were expressed in Xenopus oocytes. We determined the accessibility of the engineered cysteine to charged, sulfhydryl-specific methanethiosulfonate reagents added extracellularly. We assume that, among residues in membrane-spanning segments, only those lining the channel will be accessible to react with these hydrophilic reagents and that such a reaction would irreversibly alter conduction through the channel. Only the cysteines substituted for Gly-91, Lys-95, and Gln-98 were accessible to the reagents. We conclude that these residues are in the channel lining. The periodicity of these residues is consistent with an alpha-helical secondary structure.

Amino Acid Sequence↗

PubMed2004

Bringing new treatments to the bedside in cystic fibrosis.

The discovery of the cystic fibrosis transmembrane conductance regulator gene in 1989 led to a dramatic increase in the understanding of the molecular basis of CF. Increased knowledge has provided the opportunity to target drug development at correcting the basic defect either by gene therapy or pharmacological modulation of the abnormal physiological processes. Development of new medications for the CF population poses many challenges. The discovery and development of new medications is always time consuming and expensive. Since CF affects a small population worldwide, the potential for a drug company to profit from a new treatment is limited. In addition, each new therapy must have an additional and proven benefit to be attractive to clinicians and consumers, otherwise it will not be commercially viable. Demonstrating clinical benefit is problematic as a limited number of patients are available to participate in clinical trails and outcome measures, such as length of life, are hard to measure. In this review we will illustrate these challenges by discussing the development of treatments which have successfully reached the bedside and those that were unsuccessful.

Administration, Inhalation↗

PubMed2023

Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models.

Approximately 10% of Cystic Fibrosis (CF) patients, particularly those with CF transmembrane conductance regulator (CFTR) gene nonsense mutations, lack effective treatments. The potential of gene correction therapy through delivery of the CRISPR/Cas system to CF-relevant organs/cells is hindered by the lack of efficient genome editor delivery carriers. Herein, we report improved Lung Selective Organ Targeting Lipid Nanoparticles (SORT LNPs) for efficient delivery of Cas9 mRNA, sgRNA, and donor ssDNA templates, enabling precise homology-directed repair-mediated gene correction in CF models. Optimized Lung SORT LNPs deliver mRNA to lung basal cells in Ai9 reporter mice. SORT LNP treatment successfully corrected the CFTR mutations in homozygous G542X mice and in patient-derived human bronchial epithelial cells with homozygous F508del mutations, leading to the restoration of CFTR protein expression and chloride transport function. This proof-of-concept study will contribute to accelerating the clinical development of mRNA LNPs for CF treatment through CRISPR/Cas gene correction.

Humans↗

PubMed1992

Induction of expression of the cystic fibrosis transmembrane conductance regulator.

The cystic fibrosis transmembrane conductance regulator (CFTR) was studied in HT-29 human colonic carcinoma cells with the aim of assessing possible mechanisms of up-regulation of its expression. CFTR was identified and quantified in total cell extracts by Western immunoblots using a monoclonal anti-CFTR antibody and was functionally assessed by tracer Cl-efflux from intact cells. It was found that various stimuli that lead to a sustained (greater than or equal to 8 h) elevation of intracellular cyclic AMP elicited a marked and specific increase in CFTR expression in cell membranes and concomitant activation of Cl- secretion. Further activation of Cl- secretion was obtained by additional short term activation by cyclic AMP analogues or cyclic AMP-inducing agents. Blockers of transcription or translation largely depressed the cAMP-mediated induction of CFTR levels and associated function, indicating that the inductive phenomenon was at the transcriptional level. The results imply the involvement of putative cyclic AMP responsive (and related) elements that are present in the CFTR gene promoter and that are known to modulate eukaryotic gene expression. Activation of these elements by various stimuli might provide pharmacological tools for up-regulation of CFTR expression at both biochemical and physiological levels.

Adenocarcinoma↗

PubMed2005

Sildenafil (Viagra) corrects DeltaF508-CFTR location in nasal epithelial cells from patients with cystic fibrosis.

BACKGROUND: Most patients with cystic fibrosis (CF) have a DeltaF508 mutation resulting in abnormal retention of mutant gene protein (DeltaF508-CFTR) within the cell. This study was undertaken to investigate DeltaF508-CFTR trafficking in native cells from patients with CF with the aim of discovering pharmacological agents that can move DeltaF508-CFTR to its correct location in the apical cell membrane. METHOD: Nasal epithelial cells were obtained by brushing from individuals with CF. CFTR location was determined using immunofluorescence and confocal imaging in untreated cells and cells treated with sildenafil. The effect of sildenafil treatment on CFTR chloride transport function was measured in CF15 cells using an iodide efflux assay. RESULTS: In most untreated CF cells DeltaF508-CFTR was mislocalised within the cell at a site close to the nucleus. Exposure of cells to sildenafil (2 hours at 37 degrees C) resulted in recruitment of DeltaF508-CFTR to the apical membrane and the appearance of chloride transport activity. Sildenafil also increased DeltaF508-CFTR trafficking in cells from individuals with CF with a single copy DeltaF508 (DeltaF508/4016ins) or with a newly described CF trafficking mutation (R1283M). CONCLUSIONS: The findings provide proof of principle for sildenafil as a DeltaF508-CFTR trafficking drug and give encouragement for future testing of sildenafil and related PDE5 inhibitors in patients with CF.

Adolescent↗

PubMed2005

Carrier frequency of F508del mutation of cystic fibrosis in Indian population.

BACKGROUND: Cystic fibrosis (CF) is considered to be very rare in Indian subcontinent. Based on reports of CF in migrants from Indian subcontinent to United Kingdom and United States of America, the prevalence of CF is estimated to be between 1/10,000 and 1/40,000 in this ethnic group. The present study was done to estimate the carrier frequency of F508del mutation among neonates using cord blood samples to reflect the prevalence of CF in the study population. METHODS: 955 mothers delivering at our hospital between December 1999 and November 2000 were enrolled. Cord blood samples were analyzed for F508del mutation using polymerase chain reaction and gel electrophoresis. The frequency of patients homozygous for F508del mutation in the population was estimated using Hardy-Weinberg principle. The prevalence of CF was estimated by using the proportion of F508del homozygous cases out of all CF patients, as reported in various studies (19-44%) from Indian subcontinent. RESULTS: Out of 955 cord blood samples, 4 were positive for F508del mutation. The carrier frequency and gene frequency of F508del mutation in the Indian population was calculated to be 1/238 (0.42%) and 1/477 (0.21%), respectively. Frequency of CF patients homozygous for F508del mutation is 1/228,006. The estimated prevalence of CF is 1/43,321 to 1/100,323 in Indian population. CONCLUSION: CF does occur in Indian subcontinent though the prevalence is lesser than the Caucasian population.

Cystic Fibrosis↗

PubMed2000

Exaggerated activation of nuclear factor-kappaB and altered IkappaB-beta processing in cystic fibrosis bronchial epithelial cells.

In cystic fibrosis (CF), inflammatory mediator production by airway epithelial cells is a critical determinant of chronic airway inflammation. To determine whether altered signal transduction through the nuclear factor (NF)-kappaB pathway occurs in CF epithelial cells and results in excessive generation of inflammatory cytokines, we evaluated tumor necrosis factor (TNF)-alpha-induced production of the NF-kappaB-dependent cytokine interleukin (IL)-8 and activation of NF-kappaB in three different human bronchial epithelial cell lines: (1) BEAS cells that express wild-type CF transmembrane conductance regulator (CFTR), (2) IB3 cells with mutant CFTR, and (3) C38 cells, which are "corrected" IB3 cells complemented with wild-type CFTR. Treatment of cells with TNF-alpha (30 ng/ml) resulted in markedly elevated NF-kappaB activation and production of IL-8 by IB3 cells compared with BEAS and C38 cells. Despite the differences in NF- kappaB activation, no differences in basal levels of IkappaB-alpha or TNF-alpha- induced IkappaB-alpha processing and degradation were detected among the cell lines. In contrast, the basal level of IkappaB-beta was increased in the IB3 cells. Treatment with TNF-alpha resulted in increased formation of hypophosphorylated IkappaB-beta and increased nuclear localization of IkappaB-beta in IB3 cells compared with the other cell types. These findings provide additional evidence of a dysregulated inflammatory response in CF.

Bronchi↗

PubMed1994

Gene transfer to freshly isolated human respiratory epithelial cells in vitro using a replication-deficient adenovirus containing the human cystic fibrosis transmembrane conductance regulator cDNA.

Cystic fibrosis (CF) results from mutations of the CF transmembrane conductance regulator (CFTR) gene and subsequent defective regulation of cAMP-stimulated chloride (Cl-) permeability across the apical membrane of epithelial cells. In vitro transfer of normal CFTR cDNA corrects this defect, and studies in experimental animals have shown successful gene transfer to airway epithelium in vivo using a recombinant adenoviral vector containing the human CFTR cDNA (AdCFTR), supporting the feasibility of in vivo AdCFTR-mediated gene therapy for the respiratory manifestations of CF. One step in applying this therapy to CF patients is to evaluate the safety and efficacy of AdCFTR-mediated gene transfer in the actual target for human gene therapy, human airway epithelium. The present study demonstrates that AdCFTR restores cAMP-stimulated Cl- permeability in human CF bronchial epithelial cells. In addition, the study utilizes freshly isolated human airway epithelial cells from the nose and/or bronchi of normal individuals and/or individuals with CF to demonstrate that after in vitro AdCFTR-mediated gene transfer: (i) AdCFTR DNA does not replicate as a function of dose and time; (ii) CF epithelial cells express AdCFTR-mediated normal human CFTR mRNA; and (iii) CF epithelial cells, including terminally differentiated ciliated cells (the most common airway epithelial cell type), express the normal human CFTR protein. Together, these data support the use of AdCFTR in human gene therapy trials and suggest that biologic efficacy should be achievable in vivo.

Adenoviridae↗

PubMed1994

Abnormal subcellular localization of mutated CFTR protein in a cystic fibrosis epithelial cell line.

The cystic fibrosis gene product, CFTR, is a Cl- channel that possesses specific binding sites for cytosolic ATP and is activated by cAMP-dependent protein kinase. Most recently, it was reported that CFTR localizes at the surface apical compartment of normal airway epithelial cells, but accumulates in the cytosol of airway cells from CF patients with the delta F508 mutation. In order to explore whether the same difference exists in normal and CF established cell lines that are commonly used in physiological and pharmacological investigations of the CF defect, we employed monoclonal antibodies raised against synthetic peptides corresponding to two different regions of the CFTR protein. One antibody (MATG 1061) was generated against amino acids 503-515 delta 508 in the nucleotide binding domain 1, whereas the other (MATG 1031) was generated against amino acids 107-117 situated in a putative external loop. We used confocal laser scanning microscopy to localize the CFTR protein in T84 (a colonic derived carcinoma), CAPAN-1 (a pancreatic carcinoma), and in CFPAC-1 (a pancreatic carcinoma homozygous for the delta F508 deletion) cell lines. In permeabilized T84 and CAPAN-1 cells, immunolabeling with MATG 1061 predominated at the apical domain. By contrast, CFTR staining with MATG 1061 was homogeneously distributed in the cytoplasm of CFPAC-1 cells. In non-permeabilized non-CF cell lines, MATG 1031 specifically labeled an apical membrane surface epitope. No such labeling was present in CFPAC-1 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Line↗

PubMed1998

Liver and biliary problems in cystic fibrosis.

Liver disease associated with cystic fibrosis has been increasingly diagnosed during recent years probably due to the combined effect of systematic hepatic assessment and reduced death from extra-hepatic causes of CF patients. In a group of 173 CF patients regularly followed at our Center, cumulative incidence of liver disease was 17% over a mean period of 10 years. Although it generally runs a mild course, it is considered a major complication of CF which may limit survival and quality of life of affected patients. CF-associated liver disease should be considered as the first inherited liver disorder in which the primary defect affects cholangiocyte transport systems. Although data assessing the effects of defective CFTR on cholangiocyte pathobiology are not yet available, the impaired secretory function of the biliary epithelium is considered responsible for reduced biliary fluidity and alkalinity and for subsequent bile duct damage by cytotoxic compounds or infectious agents. No clear association with specific CFTR mutations has been observed. Treatment with ursodeoxycholic acid, aimed at improving biliary secretion in terms of bile viscosity and bile acid composition, is currently the most useful therapeutic approach in CF-associated liver disease. Beneficial effects on liver biochemistry, hepatic excretory function, liver histology, and essential fatty acid status have been reported, but no long-term data exist on its effectiveness on clinically relevant outcomes, such as death or need for transplantation. The effectiveness of bile acid therapy may be higher if started in patients with early stage liver disease, before symptoms have become clinically evident. Early diagnosis and identification of CF patients who are more liable to develop liver disease should be actively pursued.

Child↗

PubMed2006

Progression of pulmonary hyperinflation and trapped gas associated with genetic and environmental factors in children with cystic fibrosis.

BACKGROUND: Functional deterioration in cystic fibrosis (CF) may be reflected by increasing bronchial obstruction and, as recently shown, by ventilation inhomogeneities. This study investigated which physiological factors (airway obstruction, ventilation inhomogeneities, pulmonary hyperinflation, development of trapped gas) best express the decline in lung function, and what role specific CFTR genotypes and different types of bronchial infection may have upon this process. METHODS: Serial annual lung function tests, performed in 152 children (77 males; 75 females) with CF (age range: 6-18 y) provided data pertaining to functional residual capacity (FRCpleth, FRCMBNW), volume of trapped gas (VTG), effective specific airway resistance (sReff), lung clearance index (LCI), and forced expiratory indices (FVC, FEV1, FEF50). RESULTS: All lung function parameters showed progression with age. Pulmonary hyperinflation (FRCpleth > 2SDS) was already present in 39% of patients at age 6-8 yrs, increasing to 67% at age 18 yrs. The proportion of patients with VTG > 2SDS increased from 15% to 54% during this period. Children with severe pulmonary hyperinflation and trapped gas at age 6-8 yrs showed the most pronounced disease progression over time. Age related tracking of lung function parameters commences early in life, and is significantly influenced by specific CFTR genotypes. The group with chronic P. aeruginosa infection demonstrated most rapid progression in all lung function parameters, whilst those with chronic S. aureus infection had the slowest rate of progression. LCI, measured as an index of ventilation inhomogeneities was the most sensitive discriminator between the 3 types of infection examined (p < 0.0001). CONCLUSION: The relationships between lung function indices, CFTR genotypes and infective organisms observed in this study suggest that measurement of other lung function parameters, in addition to spirometry alone, may provide important information about disease progression in CF.

Adolescent↗

PubMed2006

Diagnosing and managing cystic fibrosis in the developing world.

Cystic fibrosis (CF), earlier believed to be non existent in non Caucasians, is now a pan ethnic disease, having being reported from various regions of the world over last one decade. Apart from limited resources, the major problems in diagnosis and management of CF in developing countries include: lack of awareness among pediatricians, absence of facilities for diagnosis (sweat chloride estimation and genetic studies), lack of trained manpower for care of specific problems, and non availability of appropriate drugs. Care of children with CF may not be a priority for governments in countries where childhood mortality rates are high, predominantly due to acute infections. An indigenously developed and relatively inexpensive method of sweat collection and chloride estimation using pilocarpine iontophoresis and titration, respectively, may be an alternative to the commercially available costly equipment. Having a team of trained nurse, physiotherapist, and dietician for optimal care of CF patients may not be feasible due to inadequate resources. Training a single person (e.g. nurse) to deliver comprehensive CF care may be a feasible alternative. To overcome problems of non availability of appropriate drugs (enzymes, inhaled antibiotics, DNAse, etc), locally available drugs may be used. Examples include use of hypertonic saline in place of DNAse, enteric coated enzyme tablets in place of enteric coated spherules, etc. Factors that are associated with decreased survival in CF patients from developing countries are age of onset of symptoms <2 months, severe malnutrition at the time of diagnosis, colonization with Pseudomonas at the time of diagnosis and frequency of pneumonia >4 episodes/year. All these factors can be modified except onset of symptoms before 2 months of age, by early diagnosis and appropriate treatment. Many of the above mentioned hurdles have been successfully overcome by us to establish CF services in a resource-limited setting. We conclude that education of pediatricians about the disease, early diagnosis using indigenous technology and aggressive physiotherapy with nutritional management and judicious use of antibiotics can improve the quality of life and survival in CF patients in resource-limited settings.

Anti-Bacterial Agents↗

PubMed2005

Application of multiplex ARMS and SSCP/HD analysis in molecular diagnosis of cystic fibrosis in Indian patients.

BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene. The most severe, DeltaF508, mutation accounts for nearly 70% of CF cases worldwide. Besides DeltaF508, there are other point mutations, namely G542X, G551D, R553X, N1303K, and 621+1(G-->T), which are common among Caucasians. Additionally, a polyT polymorphism in intron 8 is also involved in the pathogenesis of CF. However, neither the prevalence nor the types of mutations causing CF in India are known. In this study, we aimed at estimating the frequency of the above common mutations and polymorphism in clinically suspected CF cases. We also carried out partial analysis of the CFTR gene, limited to exons 10 and 11, to identify other variations in these exons. METHODS: The multiplex amplification refractory mutation system (ARMS) test was applied for rapid simultaneous analysis of six most common CF mutations, in 100 normal and 39 elevated sweat chloride cases. The scanning of exons 10 and 11 was carried out by single-stranded conformation polymorphism/heteroduplex (SSCP/HD) analysis, followed by DNA sequencing in 50 normal and 37 elevated sweat chloride cases. A single ARMS-polymerase chain reaction assay was used to distinguish the 5T, 7T, and 9T alleles in 100 normal and 33 elevated sweat chloride cases. RESULTS: The multiplex ARMS analysis identified the DeltaF508 mutation at an allele frequency of 24% in Indian CF cases. However, the other predominant CF mutations were found to be absent. The 7T polyT variant was observed to be the most common allele, followed by the 9T, and 5T, which was the lowest. The DeltaF508 mutation was observed in all instances with the 9T variant. The SSCP/HD and DNA sequencing additionally revealed a known polymorphism (M470V, exon 10) and a known mutation [1525-1(G-->A), intron 9]. The 1525-1(G-->A) mutation, observed in a single 4-year-old male, is predicted to code for a class II defective CFTR protein. CONCLUSION: The findings of this study suggest a difference in relative frequencies and spectrum of CFTR mutations in Indian CF cases. A larger screening study of the entire CFTR gene in clinically well defined CF cases is required to delineate common mutations in the CFTR gene and enable molecular diagnosis of CF in India.

Amino Acid Substitution↗

PubMed1995

Molecular diagnosis of cystic fibrosis.

The clinical and pathologic features of patients with cystic fibrosis are summarized, and generalized genotype or phenotype correlations are discussed in this article. Incorporation of modern molecular biologic techniques into a rapid, cost-efficient, and specific diagnostic laboratory test is outlined. The protocol for the multiplex polymerase chain reaction detection of five common cystic fibrosis transmembrane conductance regulator (CFTR) mutations by ASO hybridization is detailed. Neonatal screening and issues involved in the genetic counseling of families at risk for cystic fibrosis are presented. Recommendations for molecular diagnostic testing in cystic fibrosis are made.

Base Sequence↗

PubMed1995

The major histocompatibility complex influences the development of chronic liver disease in male children and young adults with cystic fibrosis.

BACKGROUND/AIMS: Chronic liver disease is a well-recognised complication of cystic fibrosis. Recent reports suggest that its development is not determined by specific mutations within the cystic fibrosis gene; however, familial clustering of portal hypertension cases and inappropriate immune responses against liver membrane antigens demonstrated in children with cystic fibrosis and chronic liver disease suggest that other genetic loci may be relevant. As the major histocompatibility complex has an important immunoregulatory role, we have investigated for associations with this complex and chronic liver disease in cystic fibrosis. METHODS: We have determined human leucocyte antigen class I (A and B) and class II (DR) phenotypes by serological tissue typing and class II (DR and DQ) and class III (complement component C4 and 21-hydroxylase) gene polymorphisms in 274 children and young adults with cystic fibrosis, of whom 82 had evidence of chronic liver disease with portal hypertension in 49, and 146 healthy controls. RESULTS: A marked difference in human leucocyte antigen frequency was limited to DQ6, which was found in 66.7% of cystic fibrosis patients with liver disease compared to 32.9% of patients with no liver disease (Pc < 0.03) and 28.8% of controls (Pc < 0.006). An increased frequency of the two antigens in strong linkage disequilibrium with DQ6 was also observed within this patient group, namely DR15 and B7. When the patients were stratified for the presence of portal hypertension, these observations were confirmed, but the human leucocyte antigen associations were significant only for male patients and there was no association with the age of onset of liver disease. CONCLUSIONS: These data suggest that the haplotype B7-DR15-DQ6 may carry an increased risk of development of liver disease in male cystic fibrosis patients.

Adolescent↗