Assessment of CFTR function in homozygous R117H-7T subjects

Nooijer, R.A. de; Nobel, J; Arets, H.G.M.; Bot, A.; Berkhout, F. Teding van; Rijke, Yolanda B. de; Jonge, Hugo R. de; Bronsveld, Inez

doi:10.1016/j.jcf.2011.03.009

Cited by 32 publications

(26 citation statements)

References 30 publications

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“…Studies of heterologously expressed CFTR channels by Sheppard and colleagues [12] found that the whole-cell Cl − conductance of R117H was reduced to 15% of WT, while single channel analysis found that both P O and γ were reduced predicting ∼24% WT CFTR channel function. In a male and a female each having R117H/R117H on a 7T/7T background, all clinical indices were normal except for CBAVD in the male, electrophysiological measurements of nasal and intestinal epithelia were also normal, and sweat chloride values were 34 mM for the male and 42 mM for the female [23]. However, when R117H-CFTR is in cis with a 5T allele, n = 0.1/0.7 = 14% WT, reducing R117H-5T function to 2.1–3.7% of WT function.…”

Section: Discussionmentioning

confidence: 95%

A Little CFTR Goes a Long Way: CFTR-Dependent Sweat Secretion from G551D and R117H-5T Cystic Fibrosis Subjects Taking Ivacaftor

et al. 2014

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To determine if oral dosing with the CFTR-potentiator ivacaftor (VX-770, Kalydeco) improves CFTR-dependent sweating in CF subjects carrying G551D or R117H-5T mutations, we optically measured sweat secretion from 32–143 individually identified glands in each of 8 CF subjects; 6 F508del/G551D, one G551D/R117H-5T, and one I507del/R117H-5T. Two subjects were tested only (−) ivacaftor, 3 only (+) ivacaftor and 3 (+/−) ivacaftor (1–5 tests per condition). The total number of gland measurements was 852 (−) ivacaftor and 906 (+) ivacaftor. A healthy control was tested 4 times (51 glands). For each gland we measured both CFTR-independent (M-sweat) and CFTR-dependent (C-sweat); C-sweat was stimulated with a β-adrenergic cocktail that elevated [cAMP]i while blocking muscarinic receptors. Absent ivacaftor, almost all CF glands produced M-sweat on all tests, but only 1/593 glands produced C-sweat (10 tests, 5 subjects). By contrast, 6/6 subjects (113/342 glands) produced C-sweat in the (+) ivacaftor condition, but with large inter-subject differences; 3–74% of glands responded with C/M sweat ratios 0.04%–2.57% of the average WT ratio of 0.265. Sweat volume losses cause proportionally larger underestimates of CFTR function at lower sweat rates. The losses were reduced by measuring C/M ratios in 12 glands from each subject that had the highest M-sweat rates. Remaining losses were estimated from single channel data and used to correct the C/M ratios, giving estimates of CFTR function (+) ivacaftor = 1.6%–7.7% of the WT average. These estimates are in accord with single channel data and transcript analysis, and suggest that significant clinical benefit can be produced by low levels of CFTR function.

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Section: Discussionmentioning

confidence: 95%

A Little CFTR Goes a Long Way: CFTR-Dependent Sweat Secretion from G551D and R117H-5T Cystic Fibrosis Subjects Taking Ivacaftor

et al. 2014

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“…Functional synergism was observed between STc and VX-770 (13% vs. 7% in the control group), suggesting that patient 2 might derive benefit from combination therapy with Kalydeco and a GCC agonist. The R117H Cftr, although retaining partial CFTR function, can be affected by poly-T/TG tract mutation such as in patient 2's case and may cause up to a 90% loss of CFTR function, as with the 5T variant (27,28). Importantly, a severe CF scenario has been reported to be associated with the R117H (7T/9T) variant in CFTR (29).…”

Section: Resultsmentioning

confidence: 99%

Guanylate cyclase 2C agonism corrects CFTR mutants

et al. 2017

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“…Thus, even augmentation to a low level of CFTR function may provide significant clinical benefit. For example, patients homozygous for the R117H mutation experience infertility and mildly increased sweat chloride but are completely free of any respiratory or pancreatic symptoms (De Nooijer et al, 2011). Significantly, R117H and other class IV mutations are associated with significantly lower mortality compared to class II mutations such as F508 (McKone et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Highly Efficient Repair of the ΔF508 Mutation in Airway Stem Cells of Cystic Fibrosis Patients with Functional Rescue of the Differentiated Epithelia

Vaidyanathan

et al. 2019

Preprint

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Cystic fibrosis (CF) is a monogenic autosomal recessive disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Clchannel. CF results in multiorgan dysfunction and ultimately mortality from respiratory sequelae. Although pharmacologic approaches have demonstrated efficacy in reducing symptoms and respiratory decline, a curative treatment modality remains elusive. Gene therapy, a promising curative strategy, has been limited due to poor correction efficiencies both in vitro and in vivo. Here, we use Cas9 and adeno-associated virus 6 (AAV6) to correct the F508 mutation (found in ~70% of CF alleles and ~90% of CF patients in North America) in upper airway basal stem cells (UABCs) obtained from CF and non-CF patients undergoing functional endoscopic sinus surgery (FESS). In UABCs from homozygous (F508/F508) and compound heterozygous (F508/Other) CF patients, we achieved 28  5 % and 42  15% correction, respectively. In homozygous human bronchial epithelial cells (HBECs), we achieved 41 4 % correction. Upon differentiation in air-liquid interface (ALI), cultures of corrected CF cells displayed partial restoration of CFTRinh-172 sensitive Clcurrents relative to non-CF controls: 31 5 % in UABCs and 51  3 % in HBECs (both from subjects homozygous for F508 CFTR). Finally, gene edited cells embedded successfully and retained expression of cytokeratin 5 (KRT5), a basal cell marker, on a FDA-approved porcine small intestinal submucosal (pSIS) membrane previously shown to improve re-mucosalization after FESS. In summary, we present an efficient, feederfree, selection-free and clinically compatible approach to generate cell-based therapies for CF from autologous airway stem cells. This approach represents a first step towards developing patient-specific autologous airway stem cell transplant as a curative treatment for CF.

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Assessment of CFTR function in homozygous R117H-7T subjects

Cited by 32 publications

References 30 publications

A Little CFTR Goes a Long Way: CFTR-Dependent Sweat Secretion from G551D and R117H-5T Cystic Fibrosis Subjects Taking Ivacaftor

A Little CFTR Goes a Long Way: CFTR-Dependent Sweat Secretion from G551D and R117H-5T Cystic Fibrosis Subjects Taking Ivacaftor

Guanylate cyclase 2C agonism corrects CFTR mutants

Highly Efficient Repair of the ΔF508 Mutation in Airway Stem Cells of Cystic Fibrosis Patients with Functional Rescue of the Differentiated Epithelia

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