Delta F508 Mutation Research Articles

P107 DeltaF508 mutations, age of diagnosis and age of death for patients in Bulgaria

The most common worldwide mutation for cystic fibrosis (CF) is deletion F508 (dF508). Patients homozygous for this mutation have a significantly lower median survival compared to patients carrying other mutations. In the era of newborn screening the diagnosis of patients is relatively easy and fast, while in countries without screening we rely on the clinical presentation.

Distal intestinal obstruction syndrome: a diagnostic and therapeutic challenge in cystic fibrosis

ObjectiveTo evaluate the demographics, genotype, and clinical presentation of pediatric patients presenting with distal intestinal obstruction syndrome (DIOS), and factors associated with DIOS recurrence. MethodsCase series of ten patients (median age 13.2 years), followed‐up in a reference center, retrospectively assessed. Data analyzed included age, gender, cystic fibrosis genotype, meconium ileus at birth, hydration status, pulmonary exacerbation, Pseudomonas aeruginosa colonization, pancreatic insufficiency (PI), body mass index (BMI) at the episodes, clinical manifestations of DIOS, imaging studies performed, acute management of DIOS, maintenance therapy, and recurrence on follow‐up. ResultsAll patients had two positive sweat chloride tests, and nine of ten also had genotype study. The most common genotype identified was homozygosis for the delta F508 mutation. In seven cases, a previous history of meconium ileus was reported. All patients had pancreatic insufficiency. Diagnosis of DIOS was based on clinical and imaging findings. Of the total number of episodes, 85% were successfully managed with oral osmotic laxatives and/or rectal therapy (glycerin enema or saline irrigation). Recurrence was observed in five of ten patients. ConclusionIn this first report of pediatric DIOS in South America, the presence of two risk factors for DIOS occurrence was universal: pancreatic insufficiency and severe genotype. Medical history of meconium ileus at birth was present in most patients, as well as in the subgroup with DIOS recurrence. The diagnosis relied mainly on the clinical presentation and on abdominal imaging. The practices in the management of episodes varied, likely reflecting changes in the management of this syndrome throughout time.

1481-P: Patients with Cystic Fibrosis–Related Diabetes Present with Specific Pancreatic Anomalies

Cystic fibrosis related diabetes (CFRD) is found in 20 to 50% of adults with cystic fibrosis (CF). Repeated oral glucose tolerance tests are used to screen for CFRD, but are not perfect indicators and can be tiresome for patients who already undergo many medical tests. We hypothesized that pancreatic imaging may differ between patients with and without CFRD and that the patients with the more “at-risk” pancreatic morphology could be followed more closely with the aim to detect diabetes early. We performed a non-matched case-control retrospective study comparing the abdominal ultrasounds (U.S.) and computed tomography (CT) (including abdominal slices of thoracic CT) of patients with CF with or without CFRD (“CFRD patients” and “CF patients”, respectively). Forty-four CFRD patients and 58 CF patients were included. Thirty-seven percent of the U.S. results were either uninterpretable or discordant with the CT results. Therefore, only the results of the CT were eventually analyzed. Seventy-one percent of CFRD patients presented with complete pancreatic involution (CPI), versus 57% of CF patients (p = 0.0016), and 98% of CFRD patients presented with at least partial pancreatic involution. Patients with CPI presented more frequently with exocrine pancreatic insufficiency than patients with a normal CT scan (95% versus 29%, p< 0.0001). Unexpectedly, 22% of CFRD patients presented with pancreatic calcifications, versus none of the CF patients (p = 0.0003). Patients with pancreatic calcifications did not differ from patients without, except that they were less likely to be homozygous for DeltaF508 mutation (22 versus 53%, p = 0.04). CPI is more often seen in CFRD patients than in CF patients, but is still a very frequent occurrence. A more distinctive feature is the presence of pancreatic calcifications. These might be used as a warning signal to look more closely for diabetes in patients with CF, and can be searched for on abdominal slices of routinely performed thoracic CT. Disclosure L. Alexandre-Heymann: None. M. Puerto: Other Relationship; Self; Ipsen Biopharmaceuticals. P. Burgel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Chiesi USA, Inc., Vertex Pharmaceuticals. Consultant; Self; GlaxoSmithKline plc., Pfizer Inc., Teva Pharmaceutical Industries Ltd., Zambon. Speaker’s Bureau; Self; Novartis AG. E. Larger: None.

Distal intestinal obstruction syndrome: a diagnostic and therapeutic challenge in cystic fibrosis

ObjectiveTo evaluate the demographics, genotype, and clinical presentation of pediatric patients presenting with distal intestinal obstruction syndrome (DIOS), and factors associated with DIOS recurrence. MethodsCase series of ten patients (median age 13.2 years), followed-up in a reference center, retrospectively assessed. Data analyzed included age, gender, cystic fibrosis genotype, meconium ileus at birth, hydration status, pulmonary exacerbation, Pseudomonas aeruginosa colonization, pancreatic insufficiency (PI), body mass index (BMI) at the episodes, clinical manifestations of DIOS, imaging studies performed, acute management of DIOS, maintenance therapy, and recurrence on follow-up. ResultsAll patients had two positive sweat chloride tests, and nine of ten also had genotype study. The most common genotype identified was homozygosis for the delta F508 mutation. In seven cases, a previous history of meconium ileus was reported. All patients had pancreatic insufficiency. Diagnosis of DIOS was based on clinical and imaging findings. Of the total number of episodes, 85% were successfully managed with oral osmotic laxatives and/or rectal therapy (glycerin enema or saline irrigation). Recurrence was observed in five of ten patients. ConclusionIn this first report of pediatric DIOS in South America, the presence of two risk factors for DIOS occurrence was universal: pancreatic insufficiency and severe genotype. Medical history of meconium ileus at birth was present in most patients, as well as in the subgroup with DIOS recurrence. The diagnosis relied mainly on the clinical presentation and on abdominal imaging. The practices in the management of episodes varied, likely reflecting changes in the management of this syndrome throughout time.

Cystic fibrosis presentation in del. F508 and p. Tyr109Glyfs compound heterozygote CFTR state: a case report

The diagnosis of cystic fibrosis (CF) is commonly confirmed by molecular genetics with the presence of specific mutations of cystic fibrosis transmembrane conductance regulator (CFTR) gene. We report a case of cystic fibrosis (CF) in a 15-year-old female patient who is a compound heterozygote for CFTR gene, with delta F508 and Tyr109Glyfs mutations detected. This is the first detailed description of such a case in the medical literature. The primary CF presentation occurred at the age of 9 in the form of gastrointestinal symptoms including greasy, bulky, and foul-smelling stool. The patient exhibited delayed growth, with her height and weight being below the 5th centile for age according to the World Health Organization growth curves. Pancreatic enzyme supplement treatment was started immediately, alongside high-fat and high-calorie diet, resulting in patient’s recovery and development. DNA analysis of CFTR gene demonstrated the presence of del. F508 mutation and a rare combining deletion and insertion mutation p. Tyr109Glyfs. The combination of the two mutations is very rare in CF patients and is therefore valuable to document this case in order to provide information on disease progression, therapy options, and outcomes. With standard treatment and early diagnosis, the patient is currently doing well and is not restricted by the disease in her daily and sports activities.

The Cystic Fibrosis-Like Airway Surface Layer Is not a Significant Barrier for Delivery of Eluforsen to Airway Epithelial Cells.

Background: Eluforsen (previously known as QR-010) is a 33-mer antisense oligonucleotide under development for oral inhalation in cystic fibrosis (CF) patients with the delta F508 mutation. Previous work has shown that eluforsen restores CF transmembrane conductance regulator (CFTR) function in vitro and in vivo. To be effective, eluforsen has first to reach its primary target, the lung epithelial cells. Therefore, it has to diffuse through the CF airway surface layer (ASL), which in CF is characterized by the presence of thick and viscous mucus, impaired mucociliary clearance, and persistent infections. The goal of this study was to assess delivery of eluforsen through CF-like ASL. Methods and Results: First, air-liquid interface studies with cultured primary airway epithelial cells revealed that eluforsen rapidly diffuses through CF-like mucus at clinically relevant doses when nebulized once or repeatedly, over a range of testing doses. Furthermore, eluforsen concentrations remained stable in CF patient sputum for at least 48 hours, and eluforsen remained intact in the presence of various inhaled CF medications for at least 24 hours. When testing biodistribution of eluforsen after orotracheal administration in vivo, no differences in lung, liver, trachea, and kidney eluforsen concentration were observed between mice with a CF-like lung phenotype (ENaC-overexpressing mice) and control wild-type (WT) littermates. Also, eluforsen was visualized in the airway epithelial cell layer of CF-like muco-obstructed mice and WT littermates. Finally, studies of eluforsen uptake and binding to bacteria prevalent in CF lungs, and diffusion through bacterial biofilms showed that eluforsen was stable and not absorbed by, or bound to bacteria. In addition, eluforsen was found to be able to penetrate Pseudomonas aeruginosa biofilms. Conclusions: The thickened and concentrated CF ASL does not constitute a significant barrier for delivery of eluforsen, and feasibility of oral inhalation of eluforsen is supported by these data.

Features of changes in the quality of life in cystic fibrosis patients against the background of its effective treatment

For the determination of characteristics of LQ ofpatients with cystic fibrosis (CF) and evaluation of the efficacy of the management there was used Health Utilities Index (HUI) questionnaire. The study involved 99 CF patients at the age of from 5 to 18 years. The comparison group - 102 conditionally healthy peers of the same age. All children underwent to a comprehensive medical examination and treatment. LQ assessment was carried with the aid of the HUI questionnaire. CF patients were found to have a significant decline in overall LQ in 84,8% of cases in comparison with their healthy peers. Analysis of the «way of life cohort» showed the fall in multiattribute utility indices in children at the age of 6.12 and 16 years. There was also noted a pronounced decline of indices on attributes: «pain» in 55,6%, «emotions» - in 65,6% and the «self-care» - in 20,2% of cases. Factors significantly affecting on LQ of CF patients were established to be: the presence of homozygous or heterozygous delta F508 mutation, disturbances of the respiratory function and malnutrition, which contributed to a decrease as in the overall index as well in specific aspects of LQ. Against the background of the management during the one hospitalization there was noted the positive dynamics due to the gain in the index of the emotional background. A similar situation was revealed after 6 months in re-hospitalization. Pronounced positive dynamics was noted after the management of patients with severe course of the disease, the worst values of radiological indices and a decline in FEV1 indices. The authors believe the study of LQ of CF patients to be important not only for the evaluation of the impact of the disease on the patient’s LQ, but also for the determination of the efficacy of the management.

Comparison of Homozygous for Delta F508 Mutation Nutritional Status, Lung Function Outcomes, Bacterial Growth, Antibiotic Treatments and Therapeutic Outcomes between the Amish and Non-Amish in a Single Pediatric Cystic Fibrosis Centre: A Retrospective Case-Controlled Study

There exists evident differences in the health and the care received of the Amish people in comparison to the general population. Amish patients were 100% homozygous for delta F508 mutation versus 12% in the non-Amish population (P=0.057). The Amish community was prescribed dietary supplements at a rate of 89% versus 50% for non-Amish (P=0.087). BMI > 75th percentile was 51.25% in Amish patients and 61.25% in non-Amish patients (P=0.31). Mean FEV1 value was 83.6% versus 100% while mean FEF 25-75 value was 58% versus 86% for Amish and nonAmish people respectively. There was substantial variance in the number of episodes of the same infection per patient between Amish and non-Amish population (1 IQR 0–1 versus 0 IQR 0–1; p=0.012). The rate of antibiotic prescribing per patient in the Amish group was 7.9 perceptions versus 2.2 prescriptions. The study aims to create the best possible treatment and the highest quality of life for patients with cystic fibrosis. Our manuscript creates a paradigm for future studies on the delta F508 mutation, nutrition supplements, body mass index (BMI), forced expiratory volume in 1 second (FEV1), forced expiratory flow (FEF 25-75), airway microbial organisms and changes in antibiotic treatments in Amish compared to the non-Amish group, as well as developing a platform for an Amish community health program.

Risk factors and impact of allergic bronchopulmonary aspergillosis in Pseudomonas aeruginosa-negative CF patients.

Allergic bronchopulmonary aspergillosis (ABPA) is a major complication in cystic fibrosis (CF) patients. Risk factors for ABPA and clinical deterioration in CF patients, negative for Pseudomonas aeruginosa (Pa), were explored. We performed a retrospective case-control study in 73Pa-negative patients. Each patient was matched with 2 controls for age, gender, pancreas sufficiency, DeltaF508 mutation (homozygous or heterozygous), and Pa colonization. Median FEV1 at the year of diagnosis (index year) was significantly lower in patients with ABPA. The median of cumulative values of FEV1 and FVC before the index year was not significantly different. After the index year, the median of cumulative data for FEV1 and FVC was significantly lower; there were significantly more hospitalization days and more IV antibiotic days compared to controls. Comparing pre- and post-index year data in patients with ABPA, significantly more hospitalization days and more IV antibiotic days were observed after the index year. During the period preceding the index year, significantly more ABPA patients were treated with rhDNase and inhaled corticosteroids. Bronchial damage cannot be considered as a facilitating factor for ABPA. ABPA causes a significant increase in bronchial damage. In patients with ABPA, further bronchial damage can be controlled by an increase in hospitalization days and use of IV antibiotics. rhDNase and inhaled corticosteroids were associated with the development of ABPA.

F508del CFTR gene mutation in patients with allergic bronchopulmonary aspergillosis

ABSTRACTObjective: The F508del mutation occurs in approximately 3.5% of Caucasian population of Northern Europe. Heterozygotes have increased risk for asthma and reduced pulmonary function. Allergic bronchopulmonary aspergillosis (ABPA) is more common in patients with cystic fibrosis (CF). We aimed to establish the frequency of F508del mutation in adult patients with ABPA. Methods: A retrospective matched case-control study of CF genotyped patients with ABPA seen at the National Aspergillosis Centre was undertaken. Key data were collected retrospectively from medical records, including respiratory comorbidities, total IgE, Aspergillus IgG and IgE, and immunoglobulins. Cystic fibrosis transmembrane regulator (CFTR) gene mutation analysis included multiplex PCR and sequencing. Results: From a cohort of 189 ABPA patients, 156 were screened for common mutations and variants in the CFTR gene. Eighteen were heterozygous for at least one CFTR mutation; 12 (7.7%) were heterozygous for the F508del, notably; 3 were heterozygous for the intron 8 5T variant; and 1 for an intronic variant of uncertain significance, c.3139 + 18C>T. Eight (67%) had asthma, 7 (58%) had CT-defined bronchiectasis, 4 (33%) hypergammaglobulinemia (>16 g/L), 3 (25%) sinusitis and 1 (8%) chronic pulmonary aspergillosis. Eight (67%) had elevated Aspergillus IgG antibodies (42–98 mg/L), and 8 (67%) had total IgE above 1,000 KIU/L. Two individuals heterozygous for the F508del mutation and the TG12T5 variant were diagnosed with CF, leading to a de novo CF discovery rate of 1.3%. Conclusions: In our ABPA patient cohort, the presence of the delta F508 mutation was higher than that seen in general population. Genetic counseling for CFTR genotyping might be appropriate for these patients.

Cover Image: Aquagenic wrinkling of the palms: a clue to underlying cystic fibrosis heterozygosity

Conflicts of interest: none declared. Dear Editor, Within 2 min of water immersion, this patient developed characteristic changes of aquagenic wrinkling of the palms (AWP). A rare dermatosis, AWP is distinguished by the transient appearance of white oedematous papules and plaques amid excessive wrinkling of volar skin within minutes of water exposure. It is common in cystic fibrosis (CF),1 and is reported in 9–25% of CF carriers.2 Despite having an unremarkable family history, our patient carried the often associated delta F508 mutation in CFTR. Although not validated, the timing to symptom onset may distinguish carrier status. Given the associations, CF screening and genetic testing should be considered for all patients with AWP.

Clinical and laboratory profile of children with Cystic Fibrosis: Experience of a tertiary care center in Pakistan.

Objective:To determine the clinical presentation, diagnostic investigations and laboratory workup done in admitted children with cystic fibrosis at Aga Khan University Hospital Karachi, Pakistan.Methods:This is athree years retrospective study from January 2013 to December 2015 conducted at The Aga Khan University Hospital Karachi Pakistan, enrolling admitted patient from birth to 15 years of either gender, diagnosed with CF on the basis of clinical features and positive sweat chloride test. Different clinical presentations were noted including initial presentations. Sweat chloride values more than 60mmol/L were labeled as positive and consistent with diagnosis of CF. Available Delta F-508 mutation analyses were noted. Relevant laboratory and radiological investigations including sputum culture and HR-CT chest findings were documented. Results were analyzed using SPSS version 20.Results:Total 43 children were selected according to the inclusion criteria. Chronic cough (69.76%) was the most common initial clinical presentation. Mean age at onset of symptoms was 14.41± 26.18 months and mean age at diagnosis was 47.20 ± 45.80 months Respiratory features were most common in our cohort including chronic productive cough (90.71%), recurrent bronchopneumonia (72.09%) and asthma like presentation (44.19%) with wheezing and cough. 86% patients presented with failure to thrive. Gastroenterological features including steatorrhea were seen in 55.81% patients and 44.19% patients had abdominal distension. Mean sweat chloride value in our population was 82.70± 22.74. Gene analysis for Delta F-508 was identified in 12 (27.90%) patients. Bronchiectatic pulmonary changes on HRCT were seen in 18 patients (41.86%). Pseudomonas grew in 12 patients (27.90%) in sputum cultures at the time of diagnosis.Conclusion:Respiratory presentations predominate in CF children followed by gastrointestinal features. Nearly half of our patient had bronchiectatic changes on CT scan chest and more than quarter had pseudomonas colonization in the airways at the time of diagnosis. Delta F-508 mutation was found to be uncommon in our study population. There is significant delay in diagnosing patients with CF.

Pseudo-Bartter syndrome as manifestation of cystic fibrosis with DF508 mutation

Abstract Background Pseudo Bartter syndrome (PBS) is defined as hypokalaemic hypochloraemic metabolic alkalosis in the absence of renal tubular pathology. Children with cystic fibrosis (CF) are at risk of developing electrolyte abnormalities and even PBS may occur. Case report A 5-month-old female infant with a history of two events of dehydration with vomit, refusal to eat, chronic cough, polyuria, malnutrition, metabolic alkalosis, hypokalemia, hyponatremia, hypochloremia and acute renal failure. Chronic cough study was performed, discarding pulmonary tuberculosis, gastroesophageal reflux disease and impaired swallowing. PBS was diagnosed due to hypokalaemic hypochloraemic metabolic alkalosis in the absence of renal tubular pathology. CF was corroborated by electrolytes in sweat and through molecular analysis of the delta F508 mutation. This is one of the few reported cases linking PBS and this mutation. Conclusions In patients with hyponatremic dehydration episodes with hypokalaemic hypochloraemic metabolic alkalosis, PBS should be considered as differential diagnosis. CF could be presented as PBS, mainly in patients younger than 2 years.

Nutrional status and dietary factors in cystic fibrosis patients with delta F508 mutation

Objective To examine the association between nutritional status and dietary factors in children and adolescents with cystic fibrosis that are carriers of delta F508 mutation. Methods Cross-sectional study of cystic fibrosis children and adolescents. Nutritional status (body mass index percentile) and dietary intake (3-day diet records presented as a percentage of estimated energy requirement) were assessed. Results Thirty six patients (median of 8.6; interquartile range 6.8-12.5 years; 50% male). The Poisson regression analysis showed that the carriers for delta F508 mutation had 60% lower prevalence ratio of body mass index ≥25° (PR=0.4; 95%IC=0.2-0.8) and 90% lower prevalence ratio (PR=0.1; confidence interval 95%IC=0.02-0.3) of ≥150% of estimated energy requirement when compared with non-delta F508 mutation carriers. The model was adjusted for lung function, estimated energy requirement, and body mass index. Conclusion Carriers for delta F508 mutation showed lower body mass index percentile and lower daily caloric consumption when compared with patients without this mutation.

Spontaneous bile duct perforation with cystic fibrosis and meconium ileus

Abstract Spontaneous bile duct perforation in the newborn is rare, with less than 150 cases reported. A term male newborn presented with abdominal distention and respiratory distress on the first day of life. Paracentesis revealed 420 mL of bile without succus or meconium, and laparoscopic washout and drainage was performed. A follow-up contrast enema several days later revealed a microcolon. The second operation confirmed the spontaneous bile duct perforation, but also revealed meconium ileus with ileal perforation and thick meconium. A sweat chloride study was abnormal and the patient was homozygous for the delta-F508 mutation. This is the first reported case of spontaneous bile duct perforation in association with meconium ileus or cystic fibrosis.

Genotype-phenotype relationship in Iranian patients with cystic fibrosis.

Cystic fibrosis (CF), the most common hereditary, life-threatening disease, is caused by a mutation in the CFTR gene. Because different mutations can affect clinical manifestations of patients, this study was conducted to investigate the possible genotype-phenotype relationship in a group of Iranian patients with CF. This case-series study was conducted in 30 patients with CF who were referred to a tertiary pediatric hospital in Tehran. In this study, the DNA of the patients was evaluated for delta F508 mutation, whereas some parameters such as the age at diagnosis, the sweat chloride level, and clinical manifestations related to pancreatic insufficiency and pulmonary involvement were also assessed. Among all the studied patients, 16.6% had a delta F508 mutation, either homozygote or heterozygote. The mean age at diagnosis was lower in patients with the delta F508 mutation, but the sweat chloride level tended to be higher in these patients. All the patients with the delta F508 mutation had exocrine pancreatic insufficiency, which tended to be higher than 84% in those without this mutation. In addition, all of these patients had pulmonary involvement, which tended to be higher than 64% in those with negative delta F508 mutation. According to the results of this study, the frequency of delta F508 mutations in Iranian patients appears to be much lower than what is seen in American and the European patients. In those with the delta F508 mutation, pulmonary involvement and pancreatic insufficiency are more common; the sweat chloride level tended to be higher, but the age at diagnosis was lower, all of which resemble a more severe form of disease.

Understanding Pulmonary Cystic Fibrosis

The genetic basis for cystic fibrosis is well-characterized, severe monogenic recessive disorder, that arises from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.There are several molecules that interact with CFTR gene, such as ORCC, ENaC, ROMK2, Aquaporin 3 (AQP3), NKCC1, NBC-1, Syntaxin 1A, and NHERF/EBP50. The ORCC molecule outwardly rectifies the chloride channel. Since 1989, more than 1,500 specific gene mutations and DNA sequence variations have been identified in CFTR gene. The Delta F508 mutation is the most common and is identified in almost all racial and ethnic groups ( approximately 70% of all cystic fibrosis genes). The sweat ducts of the patients are impermeable to the chloride ions, thus, the sodium chloride remains in the secretions contributing the salty sweat.Typical symptoms includes salty-tasting skin, wheezing or shortness of breath, frequent lung and par nasal sinus infections, nasal polyps, poor growth and poor weight gain, swollen belly accompanied by abdominal gas and discomfort, and broadening of the fingertips and toes. A sweat chloride concentration of more than 60 mmol/liter determined on two or more occasions by quantitative pilocarpineionophoresis remains the “gold standard” for diagnosis, but false-negative sweat tests can also be a consequence of the particular combination of CFTR mutations carried by an individual cystic fibrosis patient. The genetic testing is available, but is not commonly used because it cannot detect all gene mutations ( approximately 70-75% of the detection rate).

CFTR: a missing link between exocrine and endocrine pancreas?

CFTR: a missing link between exocrine and endocrine pancreas?

Isolated liver disease in a patient with DeltaF508/12TG-5T/M470V: A new face of an old disease

Isolated liver disease in a patient with DeltaF508/12TG-5T/M470V: A new face of an old disease

Generation of multiciliated cells in functional airway epithelium from human iPSC (1094.5)

Despite a significant improvement in the availability of therapeutic options to treat lung diseases, pulmonary disease still remains a major cause of morbidity and mortality around the world. Currently there are limited opportunities to study human lung disease either in vivo and in vitro. Using induced pluripotent stem cells (iPSC) we have generated a reproducible differentiation protocol to make mature post‐mitotic multiciliated cells in a functional airway epithelium.iPSC were generated from human skin biopsies and differentiated via FOXA2+SOX17+ definitive endoderm (>90% efficiency) to FOXA2+NKx2.1+ anterior foregut endoderm, FOXA2+NKx2.1+SOX2+ (~50% efficiency) pulmonary endoderm and then matured in an air liquid interface. Robust multiciliogenesis occurred when Notch signaling was inhibited and was confirmed by; i) the assembly of multiple pericentrin stained centrioles at the apical surface, ii) expression of transcription factor FOXJ1 and iii) presence of multiple acetylated tubulin labeled cilia projections in individual cells. The presence of NKx2.1+CC10+ Clara cells, MUC5A/C+ goblet cells and FOXA2+p63+ basal cells was also confirmed showing we are generating a complete polarized epithelial cell layer comprised of all relevant cell types. Functional cAMP activated and CFTRinh‐172 sensitive CFTR currents were recorded in isolated epithelial cells by whole cell patch clamp technique. Furthermore, we have corrected the deltaF508 mutation in the CFTR gene (>80% of all cases of CF) using a combination of CRISPR‐Cas9 endonuclease‐mediated genome editing and piggyBac transposase technologies, in the CF patient‐derived iPSC.The generation of mature multiciliated cells in a human iPSC differentiated respiratory epithelium and the ability to correct disease causing mutations provides a significant advancement toward modeling a number of human respiratory diseases in vitro.Grant Funding Source: Supported in part by CIRM and the Berger Foundation