WS18.5 Evaluation of the contributions of splicing and gating defects to dysfunction of G970R-CFTR

Fidler, Meredith C.; Sullivan, James C.; Boj, Sylvia F.; Vries, R. de; Munck, À.; Higgins, M.; Moretto-Zita, Matteo; Negulescu, Paul A.; Goor, Fredrick Van; Boeck, K. De

doi:10.1016/s1569-1993(17)30259-x

Cited by 7 publications

(6 citation statements)

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“…This favors organoids versus heterologous cell line models for the assessment of mutations and modulators on CFTR function. The results obtained for I1234V, E831X and R334W in organoids contradict observations in the FRT cells [29]. Organoid results are more in line with what is known about these mutations (see supplementary data).…”

Section: Discussionsupporting

confidence: 72%

Correction of CFTR function in intestinal organoids to guide treatment of cystic fibrosis

et al. 2020

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RationaleGiven the vast number of CFTR mutations, biomarkers predicting benefit from CFTR modulator therapies are needed for subjects with cystic fibrosis (CF).ObjectivesTo study CFTR function in organoids of subjects with common and rare CFTR mutations and evaluate correlations between CFTR function and clinical data.MethodsIntestinal organoids were grown from rectal biopsies in a cohort of 97 subjects with CF. Residual CFTR function was measured by quantifying organoid swelling induced by forskolin and response to modulators by quantifying organoid swelling induced by CFTR correctors, potentiator and their combination. Organoid data were correlated with clinical data from literature.Measurements and Main ResultsAcross 28 genotypes, residual CFTR function correlated tightly (r2=0.87) with sweat chloride values. When studying the same genotypes, CFTR function rescue by CFTR modulators in organoids correlated tightly with mean improvement in lung function (r2=0.90) and sweat chloride (r2=0.95) reported in clinical trials. We identified candidate genotypes for modulator therapy, like E92K, Q237E, R334W and L159S. Based on organoid results, two subjects started modulator treatment: one homozygous for complex allele Q359K_T360K, and the second with mutation E60K. Both subjects had major clinical benefit.ConclusionsMeasurements of residual CFTR function and rescue of function by CFTR modulators in intestinal organoids correlate closely with clinical data. Our results for reference genotypes concur with previous results. CFTR function measured in organoids can be used to guide precision medicine in patients with CF, positioning organoids as a potential in vitro model to bring treatment to patients carrying rare CFTR mutations.

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Section: Discussionsupporting

confidence: 72%

Correction of CFTR function in intestinal organoids to guide treatment of cystic fibrosis

et al. 2020

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“…The subsequent positive clinical benefit formed the basis of drug reimbursement for these subjects [40]. Conversely, there was no FIS response to ivacaftor in organoids from subjects with the G970R mutation [47] and concordantly no decrease in sweat chloride during ivacaftor treatment was seen in subjects with this mutation. These patients had been included in a clinical trial that grouped patients with rare mutations [7] presumed to belong to mutation class III based on observations in CFTR-cDNA transfected FRT cells [48].…”

Section: Intestinal Organoidsmentioning

confidence: 98%

Theranostics by testing CFTR modulators in patient-derived materials: The current status and a proposal for subjects with rare CFTR mutations

Amaral

Boeck

Davies

et al. 2019

Journal of Cystic Fibrosis

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The last decade has witnessed developments in the CF drug pipeline which are both exciting and unprecedented, bringing with them previously unconsidered challenges. The Task Force group came together to consider these challenges and possible strategies to address them. Over the last 18 months, we have discussed internally and gathered views from a broad range of individuals representing patient organizations, clinical and research teams, the pharmaceutical industry and regulatory agencies. In this and the accompanying article, we discuss two main areas of focus: i) optimising trial design and delivery for speed/efficiency; ii) drug development for patients with rare CFTR mutations. We propose some strategies to tackle the challenges ahead and highlight areas where further thought is needed. We see this as the start of a process rather than the end and hope herewith to engage the wider community in seeking solutions to improved treatments for all patients with CF.

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“…This trafficking defect was not previously observed for other types of amino acid changes observed at this position (Seibert et al, ). Despite the encouraging results obtained with transfected p.Gly970Asp‐CFTR, showing sensitivity to available drugs, we were concerned by the possibility that the underlying nucleotide change, c.2909G>A, could cause alteration of splicing as reported for c.2908G>C (Fidler et al, ). In such a case, the mutation could actually result in a grossly altered protein, thus undermining the response to the drugs.…”

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confidence: 99%

“…Recently, a study published in abstract form (Fidler et al, ) reported that c.2908G>C, putatively leading to the p.Gly970Arg mutation actually promotes an alteration of CFTR RNA splicing. Indeed, c.2908G>C involves the last nucleotide in exon 17 of CFTR gene.…”

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confidence: 99%

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Two CFTR mutations within codon 970 differently impact on the chloride channel functionality

et al. 2019

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Pharmacological rescue of mutant cystic fibrosis transmembrane conductance regulator (CFTR) in cystic fibrosis (CF) depends on the specific defect caused by different mutation classes. We asked whether a patient with the rare p.Gly970Asp (c.2909G>A) mutation could benefit from CFTR pharmacotherapy since a similar missense mutant p.Gly970Arg (c.2908G>C) was previously found to be sensitive to potentiators in vitro but not in vivo. By complementary DNA transfection, we found that both mutations are associated with defective CFTR function amenable to pharmacological treatment. However, analysis of messenger RNA (mRNA) from patient's cells revealed that c.2908G>C impairs RNA splicing whereas c.2909G>A does not perturb splicing and leads to the expected p.Gly970Asp mutation. In agreement with these results, nasal epithelial cells from the p.Gly970Asp patient showed significant improvement of CFTR function upon pharmacological treatment. Our results underline the importance of controlling the effect of CF mutation at the mRNA level to determine if the pharmacotherapy of CFTR basic defect is appropriate.

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WS18.5 Evaluation of the contributions of splicing and gating defects to dysfunction of G970R-CFTR

Cited by 7 publications

References 0 publications

Correction of CFTR function in intestinal organoids to guide treatment of cystic fibrosis

Correction of CFTR function in intestinal organoids to guide treatment of cystic fibrosis

Theranostics by testing CFTR modulators in patient-derived materials: The current status and a proposal for subjects with rare CFTR mutations

Two CFTR mutations within codon 970 differently impact on the chloride channel functionality

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