Promising new era dawns for cystic fibrosis treatment

Corbyn, Zoë

doi:10.1016/s0140-6736(12)60617-5

Cited by 13 publications

(7 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a similar manner, the compound kalydeco has been shown recently (and approved by the Food and Drug Administration) to restore trafficking of the G551D mutant of the cystic fibrosis receptor (CFTR), but it does not have a similar restorative effect on other CFTR mutants. 42 Probenecid had a restorative effect on the cell-surface trafficking of the KDF mutant but not the F14 mutant. Sobolewski et al 40 have shown that 4PBA could partially restore trafficking of the F14 mutant of BMPR2 to the cell surface in HeLa cells.…”

Section: Discussionmentioning

confidence: 91%

Subcellular Mechanisms in Pulmonary Arterial Hypertension: Combinatorial Modalities that Inhibit Anterograde Trafficking and Cause Bone Morphogenetic Protein Receptor Type 2 Mislocalization

2013

View full text Add to dashboard Cite

Abstract:The natural history of familial pulmonary arterial hypertension (PAH) typically involves mutations in and/or haploinsuffciency of BMPR2 (gene for bone morphogenetic protein receptor type 2) but with low penetrance (10%-15%), delayed onset (in the third or fourth decade), and a gender bias (two-to fourfold more prevalent in postpubertal women). Thus, investigators have sought an understanding of "second-hit" modalities that might affect BMPR2 anterograde trafficking and/or function. Indeed, vascular lung lesions in PAH have been reported to contain enlarged "vacuolated" endothelial and smooth muscle cells with dilated endoplasmic reticulum (ER) cisternae, increased ER structural protein reticulon 4 (also called Nogo-B), and enlarged and fragmented Golgi apparatus. We recently replicated this cellular phenotype in primary human pulmonary arterial endothelial cells and human pulmonary arterial smooth muscle cells in culture by acute knockdown of the estradiol 17β (E2)-responsive proteins signal transducer and activator of transcription 5a (STAT5a) and STAT5b using small interfering RNAs (siRNAs). We have now investigated whether functional haploinsufficiences of these molecules, alone or in combination with other modalities, might interfere with anterograde membrane trafficking using (a) the quantitative tsO45VSV-G-GFP trafficking assay and (b) assays for cell-surface localization of Flagtagged BMPR2 molecules. The G glycoprotein of the vesicular stomatitis virus (VSV-G) trafficking assay was validated in EA.hy926 endothelial cells by showing that cells exposed to monocrotaline pyrrole displayed reduced anterograde trafficking. Thereafter, the combinatorial knockdowns of STAT5a, STAT5b, BMPR2, and/or endothelial nitric oxide synthase as well as exposure to E2 or 2-methoxyestradiol were observed to significantly inhibit VSV-G trafficking. These combinations also led to intracellular trapping of wild-type Flag-tagged BMPR2. Overexpression of the PAH disease-derived F14 and KDF mutants of BMPR2, which were trapped in the ER/Golgi, also inhibited VSV-G trafficking in trans. zation of the KDF but not the F14 mutant. These data identify several combinatorial modalities that inhibit VSV-G anterograde trafficking and cause mislocalization of BMPR2. These modalities merit consideration in defining aspects of the late-developing and gender-biased natural history of human PAH.Keywords: vascular cell remodeling, membrane protein trafficking, tsO45VSV-G-GFP trafficking assay, monocrotaline pyrrole (MCTP), signal transducer and activator of transcription 5a/b (STAT5a/b), endothelial nitric oxide synthase (eNOS), estradiol 17β, probenecid.

show abstract

Section: Discussionmentioning

confidence: 91%

Subcellular Mechanisms in Pulmonary Arterial Hypertension: Combinatorial Modalities that Inhibit Anterograde Trafficking and Cause Bone Morphogenetic Protein Receptor Type 2 Mislocalization

2013

View full text Add to dashboard Cite

show abstract

“…International and national foundations were established in the 1950s and 1960s to share findings and advance CF's science and treatment of. In 1989, chromosome 7 was identified as the genetic basis for CF (Corbyn, 2012;Rommens et al 1989;Thursfield & Davies, 2012). This landmark discovery offered great hope and optimism that a cure would be forthcoming; however, the reality was quite different.…”

Section: Cystic Fibrosis: the Storymentioning

confidence: 99%

“…DNA mutation testing supplements the sweat test for identification of specific CF mutations. DeltaF508 is the most common mutation accounting for 90% of the CF population worldwide carrying at least one copy (Corbyn, 2012;Rommens et al, 1989;Thursfield & Davies, 2012).…”

Section: Cystic Fibrosis: the Storymentioning

confidence: 99%

“…Class-specific therapy is underway toward reaching the cure. The most exciting current scientific breakthrough is the development and Federal Drug Administration approval of a class specific drug, Ivacaftor, in April 2012 (Corbyn, 2012;Derichs, 2013). Normalization of sodium and chloride movement at the cell wall surface with Ivacaftor was reported.…”

Section: Cystic Fibrosis: the Storymentioning

confidence: 99%

“…Because of its less frequent genotype, about 4% of people with CF will benefit from this treatment, estimated to cost upward of $294,000 per person annually (Corbyn, 2012).…”

Section: Cystic Fibrosis: the Storymentioning

confidence: 99%

See 2 more Smart Citations

Hispanic Mothers’ Narratives: Experiences of Parenting a Child with Cystic Fibrosis, Health Beliefs, and Health Care Experiences Related to Cystic Fibrosis

Tirabassi-Mathis¹

View full text Add to dashboard Cite

Capturing the Direct Binding of CFTR Correctors to CFTR by Using Click Chemistry

et al. 2015

View full text Add to dashboard Cite

Cystic fibrosis (CF) is a lethal genetic disease caused by the loss or dysfunction of the CF transmembrane conductance regulator (CFTR) channel. F508del is the most prevalent mutation of the CFTR gene and encodes a protein defective in folding and processing. VX-809 has been reported to facilitate the folding and trafficking of F508del-CFTR and augment its channel function. The mechanism of action of VX-809 previously has been poorly understood. In this study, we sought to answer a fundamental question underlying the mechanism of VX-809: Does it bind CFTR directly to exert its action? We synthesized two VX-809 derivatives, ALK-809 and SUL-809, which possess an alkyne group and retain the rescue capacity of VX-809. By using a Cu(I)-catalyzed click chemistry, we provide evidence that the VX-809 derivatives bind CFTR directly in vitro and in cells. Our findings will contribute to elucidation of the mechanism of action of CFTR correctors and design of more potent therapeutics to combat CF.

show abstract

Promising new era dawns for cystic fibrosis treatment

Cited by 13 publications

References 0 publications

Subcellular Mechanisms in Pulmonary Arterial Hypertension: Combinatorial Modalities that Inhibit Anterograde Trafficking and Cause Bone Morphogenetic Protein Receptor Type 2 Mislocalization

Subcellular Mechanisms in Pulmonary Arterial Hypertension: Combinatorial Modalities that Inhibit Anterograde Trafficking and Cause Bone Morphogenetic Protein Receptor Type 2 Mislocalization

Hispanic Mothers’ Narratives: Experiences of Parenting a Child with Cystic Fibrosis, Health Beliefs, and Health Care Experiences Related to Cystic Fibrosis

Capturing the Direct Binding of CFTR Correctors to CFTR by Using Click Chemistry

Contact Info

Product

Resources

About