ABCMdb

PMID: 22878883

De Boeck K, Kent L, Davies J, Derichs N, Amaral M, Rowe S, Middleton P, de Jonge H, Bronsveld I, Wilschanski M, Melotti P, Danner-Boucher I, Boerner S, Fajac I, Southern K, de Nooijer R, Bot A, de Rijke Y, de Wachter E, Leal T, Vermeulen F, J Hug M, Rault G, Nguyen-Khoa T, Barreto C, Proesmans M, Sermet-Gaudelus I
Cftr biomarkers: time for promotion to surrogate endpoint?
Eur Respir J. 2012 Aug 9., [PubMed]

Sentences

No. Mutations Sentence Comment

94 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Tyr122* TABLE 3 Responsiveness of nasal potential difference (NPD) and sweat chloride concentration First author [ref.] Subject n and type Intervention Basal potential p-value D amiloride p-value D low chloride + isoproterenol p-value Sweat chloride Statistic The total chloride response (low chloride + isoproterenol) improves during treatment with ataluren t.i.d. in phase-II open label trials in children and adults with CF carrying at least one nonsense mutation S ERMET- G AUDELUS [19] 30 CF with nonsense mutation Ataluren 4, 4, 8 mg (14 d) NS NS 0.04 (-4.6 mV) ND Paired t-test (mean change) Ataluren 10, 10, 20 mg (14 d) NS NS 0.05 (-3.9 mV) ND K EREM [18] 53 CF with nonsense mutation Ataluren 4, 4, 8 mg (14 d) Ataluren 10, 10, 20 mg (14 d) NS NS NS NS 0.0001 (-7.1 mV) 0.03 (-3.7 mV) NS NS Paired t-test (mean change) Inconsistent findings whether systemic administration of aminoglycoside changes NPD or sweat chloride values in patients with CF Local administration of gentamycin nose drops improves NPD read-out in CF patients carrying at least one nonsense mutation 15 d intravenous gentamycin treatment S ERMET -G AUDELUS [46] 9 CF with Y122X mutation NS 0.09 (20 to 15 mV) 0.04 (-0.8 to -4.6 mV) 0.03 (109 to 85 mmol?L -1 ) Wilcoxon (mean before and after) 4 CF with other nonsense mutation NS NS NS 5 CF without nonsense mutation NS NS NS 15 d nasal aminoglycoside treatment C LANCY [47] 11 CF with nonsense mutation NS NS NS NA Paired t-test 18 CF without nonsense mutation NS NS NS NA 7 d intravenous gentamycin treatment C LANCY [48] 5 CF with nonsense mutation NS NS NS (4/5) NS GLM for repeat measures (number of patients with o1 reading o5 mV) 5 CF without nonsense mutation NS NS NS (0/5) NS 14 d gentamycin nose drops t.i.d. W ILSCHANSKI [17] 11 CF homozygous nonsense mutation 0.008 (-48 to -34 mV) 0.05 (33 to 24 mV) 0.001 (0.4 to -5.5 mV) NA t-test/MWU p-value (mean before and after) 8 CF heterozygous nonsense mutation NS NS 0.04 (-05 to -4.8 mV) NA 5 CF homozygous F508del NS NS NS NA 14 d gentamycin nose drops t.i.d. W ILSCHANSKI [49] 9 CF with nonsense mutation NS NS ,0.001 (-0.6 to -10 mV) NA MWU (mean before and after) Systemic administration of VX-770 to CF adults and children carrying at least one G551D mutation is associated with large drop in sweat chloride and a moderate improvement of total chloride response measured by NPD A CCURSO [20] 20 CF with G551D mutation VX-770 75 mg b.i.d. 14 d ND ND 0.003 (-4.7 mV) ,0.001 (-40 mEq?L -1 ) Paired t-test (mean change from baseline) VX-770 150 mg b.i.d. 14 d ND ND 0 .01 (-5.3 mV) ,0.001 (-42 mEq?L -1 ) VX-770 150 mg b.i.d. 28 d ND ND 0.02 (-3.5 mV) 0.008 (-60 mEq?L -1 ) VX-770 250 mg b.i.d. 28 d ND ND 0.05 (-5.5 mV) 0.02 (-38 mEq?L -1 ) First author [ref.] Subject n and type Intervention Basal potential p-value D amiloride p-value D low chloride + isoproterenol p-value Sweat chloride Statistic R AMSEY [50] 161 CF with G551D mutation 83 VX-770 150 mg b.i.d. 48 wks ND ND ND ,0.0001 (-49 mEq?L -1 ) MMRM (mean change from baseline through 24 wks) 78 placebo ND ND ND NS (-0.8 mEq?L -1 ) A HERNS [51] 52 CF (6-11 yrs) with G551D mutation 26 VX-770 150 mg b.i.d. 24 wks ND ND ND ,0.0001 (-56 mEq?L -1 ) MMRM (mean change from baseline through 24 wks) 26 placebo ND ND ND NS (-1.2 mEq?L -1 ) Systemic administration of VX-809 to CF patients homozygous for F508del is associated with a small, dose-dependent drop in sweat chloride C LANCY [21] 89 CF homozygous F508del mutation VX-809 25 mg q.d. 28 d ND ND NS NS Paired t-test (mean change from baseline); linear trend test p50.0013 VX-809 50 mg q.d. 28 d ND ND NS NS VX-809 100 mg q.d. 28 d ND ND NS ,0.05 (-6 mEq?L -1 ) VX-809 200 mg q.d. 28 d ND ND NS ,0.01 (-8 mEq?L -1 ) After treating patients homozygous for F508del with VX-809 for 14 days, the addition of ivacaftor 250 mg b.i.d. for 7 days is associated with a further small but statistically significant drop in sweat chloride B OYLE [52] 61 CF homozygous F508del mutation VX-809 200 mg q.d. 14 d ND ND ND ,0.01 (-4.2 mEq?L -1 ) # Paired t-test mean change from day 14 or baseline # +VX-770 150 mg b.i.d. 7 d ND ND ND NS (-2.2 mEq?L -1 ) +VX-770 250 mg b.i.d. 7 d ND ND ND p,0.001(-9.1 mEq?L -1 ) NPD parameters detect effect of treatment in phase-II trials of various modes of gene therapy K ONSTAN [53] 12 CF Compacted DNA nanoparticles in saline 0.8 mg, 2.67 mg or 8.0 mg, single dose No change ND 8 out of 12 subjects showed partial to complete response NA Descriptive N OONE [54] 11 CF EDMPC cholesterol complexed with CFTR cDNA 0.4375 mg, 1.3 mg or 4 mg total dose NS NS NS NA Paired t-test A LTON [55] 16 CF pCF1-CFTR cDNA complexed with 229 mg GL-67/DOPE/DMPE-PEG 5000 single dose NS NS NS NA MWU and Wilcoxon rank sum Z ABNER [56] 9 CF pCF1-CFTR plasmid 1.25 mg, single dose NS NS p,0.05 (3 mV to -3 mV) NA Not reported (mean before and after) pCF1-CFTR plasmid 1.25 mg complexed with 2 mg GL-67:DOPE, single dose NS NS p,0.05 (3 mV to 0.5 mV) NA TABLE 3 Continued First author [ref.] Subject n and type Intervention Basal potential p-value D amiloride p-value D low chloride + isoproterenol p-value Sweat chloride Statistic P ORTEOUS [57] 16 CF 400 mg pCMV-CFTR complexed with 2.4 mg DOTAP cationic liposome, single dose NS for group 2/8 treated patients demonstrated partial correction NS for group 2/8 treated patients demonstrated partial correction NS for group 2/8 treated patients demonstrated partial correction NA Not reported Z ABNER [58] 6 CF CFTR cDNA via adenovirus vector, single dose Sign rank statistic 2610 9 IU NS NS p50.04 (2 to -2 mV) (terbutaline) NA 6610 9 IU NS NS p50.03 (2 to -0.5 mV) (terbutaline) NA G ILL [59] 12 CF CFTR cDNA via DC-Chol/ DOPE NS NS NS NA Not reported C APLEN [60] 9 CF CFTR cDNA NS p,0.05 (+4 mV) NS NA Not reported H AY [61] 9 CF AdCFTR cDNA via adenovirus vector, single dose p50.01 (-53 to -35 mV) p50.02 (37 to 20 mV) p50.05 (-5 to -9 mV) NA Paired t-test M IDDLETON [29] 3 CF DC-Chol:DOPE NS NS NS NA Not reported No observed effect of single dose of CPX on either NPD or sweat chloride parameters M C C ARTY [62] 37 CF CPX, single dose NS NS NS NS ANOVA NPD total chloride response detects effect of Moli1901 (activator of alternative chloride channels) Z EITLIN [63] 4 CF Moli1901 (1, 3 and 10 mmol?L -1 ) NA NA ,0.05 for all doses NA Paired t-test versus vehicle NPD total chloride response detects effect of CFTR activation in patients homozygous for F508del mutation R UBENSTEIN [64] 10 CF homozygous F508del mutation Sodium 4-phenylbutu- rate 6, 6, 7 g (7 d) NS NS p50.0055 (5.2 to 0.6) NS Paired t-test (mean before and after) Basal NPD detects effect of aerosolised sodium channel blockers R ODGERS [65] 10 CF Amiloride nasal spray p,0.0001 (+20 mV) NA NA NA Two way ANOVA Benzamil nasal spray p,0.0001 (+21 mV) H OFMANN [66] 12 CF Aerosolised amiloride p,0.05 NA NA NA Independent t-test H OFMANN [67] 41 CF Aerosolised amiloride (10 -3 M) (n516) +35 mV NA NA NA No statistics Aerosolised benzamil (7610 -3 M) (n55) +35 mV TABLE 3 Continued First author [ref.] Subject n and type Intervention Basal potential p-value D amiloride p-value D low chloride + isoproterenol p-value Sweat chloride Statistic NPD detects effect of flavonoids on CFTR function P YLE [68] 12 non-CF Quercetin 20 mg:mL single dose NR p,0.05 (-7 mV) p,0.05 (-15 mV) NA ANOVA I LLEK [69] 25 non-CF Quercetin (n515), genistein (n53), kaempferol (n53), apigenin (n54) p,0.05 (-3 mV) ND ND ND Paired t-test NPD detects effect of hypertonic saline M IDDLETON [70] 7 non-CF 150 mM p,0.05 (6.6 mV) ND ND ND Paired t-test 250 mM p,0.05 (7.6 mV) 500 mM p,0.05 (10.0 mV) 1200 mM p,0.05 (13.1 mV) 2000 mM p,0.05 (14.8 mV) NPD detects effect of fluticasone propionate on epithelial sodium absorption G RAHAM [71] 6 non-CF Fluticasone propionate ND p50.03 (1.8 to 3.3 mV) NS NA Paired t-test NPD detects effect of milrinone on epithelial sodium absorption S MITH [72] 6 CF Milrinone (perfused during NPD) p,0.05 (52 to 57 mV) NS NS NA MWU Total chloride response increases in response to increased temperature B OYLE [73] 32 non-CF NS NS 0.01 (-4.4 mV) NA Paired t-test PD recorded at the end of Ringers (i.e. basal) and at the end of isoproteronol were more polarised when using agar catheter versus perfusion method S OLOMON [74] 26 non-CF p,0.05 (-15.9 versus -14.0 mV) NS p,0.05 (-31.2 versus -24.8 mV) NA Paired t-test Basal NPD and amiloride response detects effect of moderate exercise A LSUWAIDAN [75] 7 CF Cycle ergometer exercise at 80% HR peak p,0.05 ND ND ND Paired t-test H EBESTREIT [76] 9 CF Cycle ergometer exercise at 85% of VT p,0.01 (-34 to -7 mV) p,0.01 (+26 to +16 mV) NS ND Paired t-test CF: cystic fibrosis; NS: nonsignificant; ND: no data; NA: not applicable; GLM: generalised linear model; MWU: Mann-Whitney U-test; MMRM: mixed-effects models for repeated measurements; NR: not reported; HR peak : peak heart rate, VT: ventilatory threshold. Login to comment 134 ABCC7 p.Gly551Asp Marked changes in sweat chloride occurred after administration of the CFTR potentiator ivacaftor to CF subjects with the G551D mutation (20, 54). Login to comment 140 ABCC7 p.Gly551Asp Marked changes in sweat chloride occurred after administration of the CFTR potentiator ivacaftor to cystic fibrosis subjects with the G551D mutation [20, 50]. Login to comment 220 ABCC7 p.Gly551Asp ABCC7 p.Tyr122* 15d intravenous gentamycin treatment 9 CF with Y122X mutation NS 0.09 (20 to 15mV) 0.04 (‐0.8 to ‐4.6mV) 0.03 (109 to 85 mmol/L) Wilcoxon (mean before and after) (74) 4 CF with other nonsense mutation NS NS NS 5 CF without nonsense mutation NS NS NS 15d nasal aminoglycoside treatment 11 CF with nonsense mutation NS NS NS NA paired t‐test (75) 18 CF without nonsense mutation NS NS NS NA 7d intravenous gentamycin treatment 5 CF with nonsense mutation NS NS NS (/5) NS GLM for repeat measures (76) 5 CF without nonsense mutation NS NS NS (0/5) NS (#patients with ≥1 reading ≥5mV) 14d gentamycin nose drops TID 11 CF homozygous nonsense mutation 0.008 (‐48 to ‐ 34mV) 0.05 (33 to 24mV) 0.001 (0.4 to ‐5.5mV) NA t‐test/MWU p value (mean before and after) (17) 8 CF heterozygous nonsense mutation NS NS 0.04 (‐.05 to ‐4.8mV) NA 5 CF homozygous F508del NS NS NS NA 14d gentamycin nose drops TID 9 CF with nonsense mutation NS NS <0.001 (‐0.6 to ‐10mV) NA MWU (mean before and after) (77) Systemic administration of VX‐770 to CF adults and children carrying at least 1 G551D mutation is associated with large drop in sweat chloride and a moderate improvement of total chloride response measured by NPD. Login to comment 221 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp 20 CF with G551D mutation paired t‐test (mean change from baseline) (20) VX‐770 75mg BID 14d ND ND 0.003 (‐4.7mV) <0.001 (‐ 40mEq/L) VX‐770 150mg BID 14d ND ND 0 .01 (‐5.3mV) <0.001 (‐ 42mEq/L) VX‐770 150mg BID 28d ND ND 0.02 (‐3.5mV) 0.008 (‐ 60mEq/L) VX‐770 250mg BID 28d ND ND 0.05 (‐5.5mV) 0.02 (‐38mEq/L) 161 CF with G551D mutation (54) 83 VX770 150mg BID 48wks 78 placebo ND ND ND ND ND ND <0.0001 (‐ 49mEq/L) NS (‐0.8mEq/)L MMRA (mean change from baseline through 24 wks) 52 CF (6‐11 yrs) with G551D mutation 26 VX770 150mg BID 24wks 26 placebo ND ND ND ND ND ND <0.0001 ( ‐ 56mEq/L) NS (‐1.2 mEq/L) MMRA (mean change from baseline (62) through 24 wks) Systemic administration of VX‐809 to CF patients homozygous for F508del is associated with a small, dose dependent drop in sweat chloride 89 CF homozygous F508del mutation paired t‐test (mean change from baseline) *Linear trend test p.0013 (78) VX‐809 25 mg QD 28d ND ND NS NS VX‐809 50 mg QD 28d ND ND NS NS VX‐809 100mg QD 28d ND ND NS <0.05 (‐6 mEq/L) VX‐809 200mg QD 28d ND ND NS <0.01 (‐8mEq/L) After treating patients homozygous for F508del with VX‐809 for 14 days, the addition of ivacaftor 250 mg BID during 7 days, is associated with a further small but statistically significant drop in sweat chloride 61 CF homozygous F508del mutation (55) VX‐809 200mg QD 14d; +VX‐770 150mg BID7d +VX‐770 250mg BID7d ND ND ND ND ND ND ND ND ND <0.01 (‐4.2 mEq/L)* NS (‐2.2 mEq/L) P<.001(‐9.1 mEq/L) paired t test mean change from D14 or baseline* NPD parameters detect effect of treatment in Phase II trials of various modes of gene therapy 12 CF (79) Compacted DNA nanoparticles in saline 0.8mg, 2.67mg, or 8.0mg, single dose No change NR 8 out of 12 subjects showed partial to complete response NA Descriptive 11 CF (80) EDMPC cholesterol complexed with CFTR cDNA 0.4375mg, 1.3mg or 4mg total dose NS NS NS NA Paired t‐test 16 CF MWU & Wilcoxin rank sum (81) pCF‐1‐CFTR cDNA complexed with 229mg GL‐67/DOPE/DMPE‐PEG5000 single dose NS NS NS NA 9 CF (82) pCF1‐CFTR plasmid 1.25mg, single dose NS NS p<0.05 (3mV to ‐3mV) NA not reported (mean before and after) pCF1‐CFTR plasmid 1.25mg complexed with 2mg GL‐67:DOPE, single dose NS NS p<0.05 (3mV to 0.5mV) NA 16 CF (83) 400μg pCMV‐CFTR complexed with 2.4mg DOTAP cationic liposome, single dose NS for group 2/8 treated patients demonstrated partial correction NS for group 2/8 treated patients demonstrated partial correction NS for group 2/8 treated patients demonstrated partial correction NA Not reported 6 CF sign rank statistic (84) CFTR cDNA via adenovirus vector, single dose 2x109 I.U. NS NS p=0.04 (2 to ‐2mV)*terb NA 6x109 I.U. NS NS p=0.03 (2 to ‐0.5mV) *terb NA 12 CF not reported (85) CFTR cDNA via DC‐Chol/DOPE NS NS NS NA 9 CF not reported (86) CFTR cDNA NS p<0.05 (+4mV) NS NA 9 CF paired t‐test (87) AdCFTR cDNA via adenovirus vector, single dose p=0.01 (‐53 to ‐35mV) p=0.02 (37 to 20mV) p=0.05 (‐5 to ‐9mV) NA 3 CF not reported (29) DC‐Chol:DOPE NS NS NS NA No observed effect of single dose of CPX on either NPD or sweat chloride parameters 37 CF ANOVA (88) CPX, single dose NS NS NS NS NPD total chloride response detects effect of Moli1901 (activator of alternative chloride channels) 4 CF paired t‐test vs. vehicle (89) Moli1901 (1, 3 and 10μmol/L) NA NA <0.05 for all doses NA NPD total chloride response detects effect of CFTR activation in patients homozygous for F508del mutation 10 CF homozygous F508del mutation paired t‐test (mean before and after) (90) sodium 4‐phenylbuturate 6, 6, 7g (7d) NS NS p=0.0055 (5.2 to 0.6) NS Basal NPD detects effect of aerosolised sodium channel blockers 10 CF Two way ANOVA (91) Amiloride nasal spray p<0.0001 (+20mV) NA NA NA Benzamil nasal spray p<0.0001 (+21mV) 12 CF Independent t‐ test (92) Aerosolised amiloride p<0.05 NA NA NA 41 CF no statistics (93) (n=16) Aerosolised amiloride (10‐3 M) +35mV NA NA NA (n=5) Aerosolised benzamil (7x10‐3 M) +35mV NPD detects effect of flavonoids on CFTR function 12 non‐cf ANOVA (94) Quercetin 20µg:mL single dose NR P<0.05 (‐7mV) P<0.05 (‐15mV) NA 25 non‐cf (n=15) quercetin, (n=3) genistein, (n=3) kaempferol, (n=4) apigenin P<0.05 (‐3mV) ND ND ND Paired t‐test (95) NPD detects effect of hypertonic saline 7 non‐CF paired t‐test (96) 150mM p<0.05 (6.6mV) ND ND ND 250mM p<0.05 (7.6mV) 500mM p<0.05 (10.0mV) 1,200mM p<0.05 (13.1mV) 2,000mM p<0.05 (14.8mV) NPD detects effect of fluticasone propionate on epithelial sodium absorption 6 non‐CF Fluticasone propionate ND p=0.03 (1.8 to 3.3 mV) NS NA paired t‐test (97) NPD detects effect of milrinone on epithelial sodium absorption 6 CF MWU (98) Milrinone (perfused during NPD) p<0.05 (52 to 57mV) NS NS NA Total chloride response increases in response to increased temperature 32 non‐CF NS NS 0.01 (‐4.4mV) NA paired t‐test (99) PD recorded at the end of Ringers (i.e. basal) and at the end of isoproteronol were more polarised when using agar catheter versus perfusion method 26 non‐CF p<0.05 (‐15.9 vs. ‐14.0mV) NS p<0.05 (‐31.2 vs. ‐ 24.8mV) NA paired t‐test (100) Basal NPD and amiloride response detects effect of moderate exercise 7 CF paired t‐test (101) Cycle ergometer exercise at 80%HRpeak p<0.05 ND ND ND 9 CF paired t‐test (102) Cycle ergometer exercise at 85% of VT p<0.01 (‐34 to ‐7mV) p<0.01 (+26 to +16mV) NS ND Abbreviations: HRpeak = peak heart rate, VT = ventilatory threshold, NA = not applicable Subject type: CF subjects with a specific mutation can be homozygous or heterozygous for this mutation unless specifically stated. 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