Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis

Patel, Sanjay R.; Sinha, Ian; Dwan, Kerry; Echevarria, Carlos; Schechter, Michael S.; Southern, Kevin W

doi:10.1002/14651858.cd009841.pub2

Cited by 33 publications

(20 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This drug can be used for patients who have one of the 33 mutations of classes III and IV - among them, mutations G551D, R347H and 1152H, present in three patients (7.14%) of this study. 30 - 33 …”

Section: Discussionmentioning

confidence: 99%

Genetic and phenotypic traits of children and adolescents with cystic fibrosis in Southern Brazil

et al. 2018

View full text Add to dashboard Cite

Objectives: To characterize the main identified mutations on cystic fibrosis transmembrane conductance regulator (CFTR) in a group of children and adolescents at a cystic fibrosis center and its association with the clinical and laboratorial characteristics. Method: Descriptive cross-sectional study including patients with cystic fibrosis who had two alleles identified with CFTR mutation. Clinical, anthropometrical, laboratorial and pulmonary function (spirometry) data were collected from patients’ records in charts and described with the results of the sample genotyping. Results: 42 patients with cystic fibrosis were included in the study. The most frequent mutation was F508del, covering 60 alleles (71.4%). The second most common mutation was G542X (six alleles, 7.1%), followed by N1303K and R1162X mutations (both with four alleles each). Three patients (7.14%) presented type III and IV mutations, and 22 patients (52.38%) presented homozygous mutation for F508del. Thirty three patients (78.6%) suffered of pancreatic insufficiency, 26.2% presented meconium ileus, and 16.7%, nutritional deficit. Of the patients in the study, 59.52% would be potential candidates for the use of CFTR-modulating drugs. Conclusions: The mutations of CFTR identified more frequently were F508del and G542X. These are type II and I mutations, respectively. Along with type III, they present a more severe cystic fibrosis phenotype. More than half of the sample (52.38%) presented homozygous mutation for F508del, that is, patients who could be treated with Lumacaftor/Ivacaftor. Approximately 7% of the patients (7.14%) presented type III and IV mutations, therefore becoming candidates for the treatment with Ivacaftor.

show abstract

Section: Discussionmentioning

confidence: 99%

Genetic and phenotypic traits of children and adolescents with cystic fibrosis in Southern Brazil

et al. 2018

View full text Add to dashboard Cite

show abstract

“…3,55 These heterozygote individuals express 50% of the normal amount of CFTR protein and secrete 50% of the airway surface fluid and chloride ions compared to healthy non-CF individuals. 56,57 However, heterozygote humans and mice do not exhibit pathological symptoms. [58][59][60] Furthermore, it is important to note that increasing the expression of F508del-CFTR in only 10% of CF epithelial cells is sufficient to improve the level of CFTR-mediated chloride ion transport.…”

Section: Discussionmentioning

confidence: 99%

Elevated Mirc1/Mir17-92 cluster expression negatively regulates autophagy and CFTR (cystic fibrosis transmembrane conductance regulator) function in CF macrophages

et al. 2016

View full text Add to dashboard Cite

Cystic fibrosis (CF) is a fatal, genetic disorder that critically affects the lungs and is directly caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR function. Macroautophagy/autophagy is a highly regulated biological process that provides energy during periods of stress and starvation. Autophagy clears pathogens and dysfunctional protein aggregates within macrophages. However, this process is impaired in CF patients and CF mice, as their macrophages exhibit limited autophagy activity. The study of microRNAs (Mirs), and other noncoding RNAs, continues to offer new therapeutic targets. The objective of this study was to elucidate the role of Mirs in dysregulated autophagy-related genes in CF macrophages, and then target them to restore this host-defense function and improve CFTR channel function. We identified the Mirc1/Mir17-92 cluster as a potential negative regulator of autophagy as CF macrophages exhibit decreased autophagy protein expression and increased cluster expression when compared to wild-type (WT) counterparts. The absence or reduced expression of the cluster increases autophagy protein expression, suggesting the canonical inverse relationship between Mirc1/Mir17-92 and autophagy gene expression. An in silico study for targets of Mirs that comprise the cluster suggested that the majority of the Mirs target autophagy mRNAs. Those targets were validated by luciferase assays. Notably, the ability of macrophages expressing mutant F508del CFTR to transport halide through their membranes is compromised and can be restored by downregulation of these inherently elevated Mirs, via restoration of autophagy. In vivo, downregulation of Mir17 and Mir20a partially restored autophagy expression and hence improved the clearance of Burkholderia cenocepacia. Thus, these data advance our understanding of mechanisms underlying the pathobiology of CF and provide a new therapeutic platform for restoring CFTR function and autophagy in patients with CF.

show abstract

“…This requires a better understanding of the interactions between the exocrine and endocrine pancreas. Recent studies, using CFTR correctors, demonstrate proof of principal that restoration of secretion is possible 42–44 . Novel and minimally invasive gene manipulation techniques developed in animal models can be translated to humans 45 .…”

Section: Exocrine Complications Of Chronic Pancreatitismentioning

confidence: 99%

Chronic Pancreatitis in the 21st Century - Research Challenges and Opportunities

et al. 2016

View full text Add to dashboard Cite

A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to focus on research gaps and opportunities in chronic pancreatitis (CP) and its sequelae. This conference marked the 20th year anniversary of the discovery of the cationic trypsinogen (PRSS1) gene mutation for hereditary pancreatitis. The event was held on July 27, 2016, and structured into 4 sessions: (1) pathophysiology; (2) exocrine complications; (3) endocrine complications; and (4) pain. The current state of knowledge was reviewed; many knowledge gaps and research needs were identified that require further investigation. Common themes included the need to design better tools to diagnose CP and its sequelae early and reliably, identify predisposing risk factors for disease progression, develop standardized protocols to distinguish type 3c diabetes mellitus from other types of diabetes and design effective therapeutic strategies through novel cell culture technologies, animal models mimicking human disease, and pain management tools. Gene therapy and cystic fibrosis conductance regulator (CFTR) potentiators as possible treatments for CP were discussed. Importantly, the need for chronic pancreatitis endpoints and intermediate targets for future drug trials was emphasized.

show abstract

Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis

Cited by 33 publications

References 56 publications

Genetic and phenotypic traits of children and adolescents with cystic fibrosis in Southern Brazil

Genetic and phenotypic traits of children and adolescents with cystic fibrosis in Southern Brazil

Elevated Mirc1/Mir17-92 cluster expression negatively regulates autophagy and CFTR (cystic fibrosis transmembrane conductance regulator) function in CF macrophages

Chronic Pancreatitis in the 21st Century - Research Challenges and Opportunities

Contact Info

Product

Resources

About