In vitro pharmacologic restoration of CFTR-mediated chloride transport with sodium 4-phenylbutyrate in cystic fibrosis epithelial cells containing delta F508-CFTR.

Rubenstein, Ronald C.; Egan, Marie E.; Zeitlin, Pamela L.

doi:10.1172/jci119788

Cited by 356 publications

(273 citation statements)

References 34 publications

Supporting

Mentioning

260

Contrasting

Unclassified

Order By: Relevance

“…These included drugs approved for non-CF indications [e.g., 4-phenylbutyrate, miglustat, sildenafil, suberoylanilide hydroxamic acid (SAHA)] (19,(30)(31)(32) and compounds identified through high-throughput screening (e.g., corr-4a, VRT-325) (18,19). The cultured F508del-HBE cells were preincubated with each compound at the maximally effective concentration and treatment duration (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Several CFTR correctors have been previously reported to be active in vitro, including drugs approved for non-CF indications (e.g., 4-phenylbutyrate, miglustat, sildenafil, SAHA) (19,(30)(31)(32) and compounds identified through high-throughput screening (e.g., corr-4a, VRT-325) (18,19). Therapies for CF have not advanced from these efforts, possibly due to insufficient restoration of CFTR function and/or poor selectivity for processing of CFTR compared with other proteins and other off-target actions.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809

Goor

Hadida

Grootenhuis

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

973

985

View full text Add to dashboard Cite

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator ( CFTR ) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amounts of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small molecules. Here we describe the in vitro pharmacology of VX-809, a CFTR corrector that was advanced into clinical development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approximately 14% of non-CF human bronchial epithelial cells (EC 50 , 81 ± 19 nM), a level associated with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR corrected by VX-809 exhibited biochemical and functional characteristics similar to normal CFTR, including biochemical susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809

Goor

Hadida

Grootenhuis

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

973

985

View full text Add to dashboard Cite

show abstract

“…4-PBA restores the proper trafficking of several classes of misfolded proteins, including mutant Cx50 , CFTR-F508 (Rubenstein et al 1997), p-Z-α1-antitrypsin (Burrows et al 2000) and mutant surfactant protein C (Wang et al 2003). Given this, we tested whether 4-PBA could compensate for Cx43-HKKSL overexpression by 3(3).…”

Section: Discussionmentioning

confidence: 99%

Identification of rab20 as a Potential Regulator of Connexin43 Trafficking

Sarma

Kaplan

Willemsen

et al. 2008

Cell Communication & Adhesion

View full text Add to dashboard Cite

Connexin oligomerization and trafficking are regulated processes. To identify proteins that control connexin43 (Cx43), a screen was designed using HeLa cells expressing a Cx43 construct with di-lysine endoplasmic reticulum (ER)-retention/retrieval motif, Cx43-HKKSL. At moderate levels of expression, Cx43-HKKSL is retained in the ER as monomers; however, Cx43-HKKSL stably overexpressed by HeLa cells localizes to the perinuclear region and oligomerizes. HeLa/Cx43-HKKSL overexpressors were transiently transfected with pooled clones from a human kidney cDNA library and used immunofluorescence microscopy to identify cDNAs that enabled overexpressed Cx43-HKKSL to convert from a perinuclear to ER localization pattern. Using this approach, a small molecular weight GTPase, rab20, was identified as a candidate protein with the ability to regulate Cx43 trafficking. Enhanced green florescent protein (EGFP)-tagged rab20 showed a predominantly perinuclear and ER localization pattern and caused wild-type Cx43 to be retained inside the cell. By contrast, mutant EGFP-rab20T19N, which lacks the ability to bind GTP, had no effect on Cx43. These results suggest Cx43 is transported through an intracellular compartment regulated by rab20 along the secretory pathway.

show abstract

“…One of the methods being explored as a potential treatment of CFTR ⌬F508 patients is to administer drugs (such as sodium 4-phenylbutyrate) which are capable of trafficking the mutated protein to the apical membrane by inhibiting the binding to the molecular chaperons in the ER. [21][22][23] After clarifying the mechanism for the intracellular retention of E297G and D482G BSEP, it is possible to identify agents able to target these mutated BSEP molecules to the apical surface. Because both of the mutated BSEP molecules per se are associated with normal transport functions, it may be possible to treat these PFIC2 patients with such agents.…”

Section: Discussionmentioning

confidence: 99%

Two common PFIC2 mutations are associated with the impaired membrane trafficking of BSEP/ABCB11

et al. 2005

View full text Add to dashboard Cite

In vitro pharmacologic restoration of CFTR-mediated chloride transport with sodium 4-phenylbutyrate in cystic fibrosis epithelial cells containing delta F508-CFTR.

Cited by 356 publications

References 34 publications

Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809

Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809

Identification of rab20 as a Potential Regulator of Connexin43 Trafficking

Two common PFIC2 mutations are associated with the impaired membrane trafficking of BSEP/ABCB11

Contact Info

Product

Resources

About