ABCMdb

PMID: 19627168

Rowe SM, Clancy JP
Pharmaceuticals targeting nonsense mutations in genetic diseases: progress in development.
BioDrugs. 2009;23(3):165-74. doi: 10.2165/00063030-200923030-00003., [PubMed]

Sentences

No. Mutations Sentence Comment

477 ABCC7 p.Trp1282* As an example of this effect, mRNA levels from the W1282X CFTR allele were restored during aminoglycoside treatment, suggesting that the relationships between PTC readthrough and mRNA stabilization may exist in mammalian cells. Login to comment 484 ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Gly542* ABCC7 p.Arg1162* [26] They extended this work to the four most common disease-causing mutations in CFTR (G542X, R553X, R1162X, and W1282X), including studies in an immortalized lower airway cell line (IB3-1) isolated from a CF patient heterozygous for the W1282X CFTR mutation. Login to comment 518 ABCC7 p.Gly542* Suppression of PTCs in Animal Models Two mouse models have been developed that possess PTCs in disease-causing genes, including the mdx mouse (a model of muscular dystrophy) and the transgenic G542X-hCFTR mouse (a model of CF). Login to comment 522 ABCC7 p.Gly542* ABCC7 p.Gly542* Complementary studies in the G542X-hCFTR mouse (expressing the human G542X CFTR cDNA under regulatory control of the FABP promoter on a Cftr knockout background) confirmed that gentamicin treatment increased the detection of full-length CFTR protein in the gut (the site of CF-related mortality in this genetic model) and was associated with the appearance of cAMP-stimulated Cl-conductance in isolated gut tissue studied ex vivo. Login to comment 524 ABCC7 p.Gly542* Follow-up studies confirmed these effects and extended the findings to clinically relevant doses of both gentamicin and amikacin; amikacin suppressed the G542X-hCFTR premature stop mutation more effectively than gentamicin at clinically relevant doses. Login to comment 530 ABCC7 p.Gly542* [24] In the G542X-hCFTR mouse, oral and intraperitonealadministration led to detectable full-length CFTR localization at the apical cell membrane of gut glandular cells by immunofluorescent staining, and improved Cl-conductance as assayed by transepithelial ion transport. Login to comment 532 ABCC7 p.Trp1282* ABCC7 p.Arg1162* In the oral and parenteral experiments investigating PTC124 in the CF mouse model, correction of X X CFTR with PTC Unstable mRNA Stabilized mRNA Truncated CFTR (partial activity) W1282X Suppressor agents Genetic modifiers Transcription represents the PTC within the mRNA transcript NMD Baseline expression NMD modifiers Degraded mRNA Truncated CFTR (nonfunctional) ࢏ Faithful translation ࢏ Readthrough (+suppressors) + CFTR potentiator X R1162X Full-length CFTR Full-length (nonfunctional) OR S S S S S CFTR potentiator Full-length CFTR Full-length (nonfunctional) OR S S Suppressor agents 1 2 3 3 3 2 +/- +/- + + + + + + represents PTC Fig. 1. Login to comment 541 ABCC7 p.Trp1282* ABCC7 p.Arg1162* Again, this truncated CFTR may be functional (e.g. W1282X CFTR) or nonfunctional (e.g. R1162X CFTR). Login to comment 556 ABCC7 p.Trp1282* In both studies, the vast majority of patients with PTCs harbored at least one copy of the W1282X CFTR allele, a mutation highly prevalent in CF patients of Ashkenazi Jewish descent. Login to comment 559 ABCC7 p.Tyr122* Sermet-Gaudelus et al.,[52] recently reported correction of CFTR-dependent Cl-conductance, as measured by NPD, following 15 days of systemic treatment with gentamicin in six of nine CF patients with the Y122X mutation (eight of nine were homozygous). Login to comment 561 ABCC7 p.Tyr122* Notably, the sweat Cl-concentration improved from a mean of 109 mEq at baseline to 85mEq in CF patients with the Y122X mutation, following treatment with gentamicin (see further discussion of related studies below). Login to comment 567 ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Arg1162* In in vitro experiments comparing the R1162X (found immediately prior to the second nucleotide binding domain of CFTR) and W1282X CFTR (found within the second nucleotide binding domain) premature termination codons, W1282X CFTR was noted to be more susceptible to readthrough and exhibited partial activity in the truncated state. Login to comment 568 ABCC7 p.Trp1282* ABCC7 p.Arg1162* ABCC7 p.Arg1162* This was seen despite the presence of common UGA PTCs in both mutations and a +4 codon in the R1162X CFTR that would suggest relative susceptibility to readthrough [W1282X PTC is UGA-A, whereas the R1162X PTC is UGA-G]). Login to comment 569 ABCC7 p.Trp1282* [59] The results suggest that synthesis of both full-length protein (through PTC suppression) and truncated protein (through stabilization of mRNA) could contribute to CFTR rescue in CF patients harboring W1282X CFTR; alternatively, patients with this mutation might be more sensitive to readthrough. Login to comment 571 ABCC7 p.Trp1282* ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Tyr122* A rank order of Y122X, W1282X, G542X, and R1162X was seen among the most frequent stop mutations after gentamicin treatment, with relative suppression varying by as much as 7.2-fold, post-therapy. Login to comment 585 ABCC7 p.Trp1282* ABCC7 p.Gly542* [60] The detection of rescued CFTR activity in several patients with the G542X CFTR mutation (and others) in the studies conducted in Israel[55] and France/ Belgium,[64] suggests that the treatment effect is not limited to individuals with the W1282X mutation and that the agent can potentially exhibit a broad spectrum of activity across multiple PTCs in vivo. Login to comment