Clinical effects of the three CFTR potentiator treatments curcumin, genistein and ivacaftor in patients with the CFTR-S1251N gating mutation

Berkers, Gitte; Meer, Renske van der; Mourik, Peter van; Vonk, Annelotte M.; Kruisselbrink, Evelien; Suen, S.W.F.; Heijerman, H.G.M.; Majoor, Christof J.; Koppelman, Gerard H.; Roukema, Jolt; Janssens, Hettie M.; Rijke, Yolanda B. de; Kemper, E. Marleen; Beekman, Jeffrey M.; Ent, Cornelis K. van der; Jonge, Hugo R. de

doi:10.1016/j.jcf.2020.04.014

Cited by 15 publications

(16 citation statements)

References 33 publications

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“…As part of an investigator initiated clinical trial (Berkers et al [7] ), we studied the plasma levels of ivacaftor in samples from 16 patients, who were treated with ivacaftor 150 mg twice daily. After 8 weeks of treatment, change from baseline in lung function (FEV1% predicted) and SCC were measured as well as plasma ivacaftor levels.…”

Section: Methodsmentioning

confidence: 99%

Breast development in a 7 year old girl with CF treated with ivacaftor: An indication for personalized dosing?

Jeyaratnam

Meer

Berkers

et al. 2021

Journal of Cystic Fibrosis

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Substantial progress has been made in the treatment of Cystic fibrosis due to introduction of CFTR modulators. However, little is known about the long term side effects of treatment with these drugs. We here present a 7 year old girl with CF who presented with breast development as a rare dose dependent side effect of treatment with ivacaftor and we report data on the correlation between drug plasma concentration and clinical effect, bodyweight, and BSA in 16 patients.Higher plasma concentrations did not correlate with clinical effect, as change in FEV1 and sweat chloride concentration. Patients with low bodyweight or BSA tended to have higher plasma concentrations. This might indicate that the current recommended dose of ivacaftor is at the top of the dose-response curve and that some patients can be treated with lower doses of ivacaftor with similar clinical effect.

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Section: Methodsmentioning

confidence: 99%

Breast development in a 7 year old girl with CF treated with ivacaftor: An indication for personalized dosing?

Jeyaratnam

Meer

Berkers

et al. 2021

Journal of Cystic Fibrosis

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“…The potentiator synergy observed in our dual potentiator combinations supports our hypothesis that G1837 may have additional binding sites or mechanisms of action to VX-770. While VX-770 has been shown to provide clinical benefit to patients with responsive mutations ( Berkers et al., 2020 ; McKone et al., 2014 ; Volkova et al., 2020 ), it does not restore the Po of gating defect mutants (G551D-CFTR) to full WT-CFTR activity ( Van Goor et al., 2009 ). This opens the possibility that using another potentiator with a different mechanism of action could complement VX-770 activity and increase CFTR activity beyond that of VX-770 monotherapy.…”

Section: Discussionmentioning

confidence: 99%

Molecular dynamics and functional characterization of I37R-CFTR lasso mutation provide insights into channel gating activity

et al. 2022

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“…The potentiator synergy observed in our dual potentiator combinations supports our hypothesis that G1837 may have additional binding sites or mechanisms of action to VX-770. While VX-770 has been shown to provide clinical benefit to patients with responsive mutations (McKone et al 2014;Volkova et al 2020;Berkers et al 2020), it does not restore the Po of gating defect mutants (G551D-CFTR) to full WT-CFTR activity (Van Goor et al 2009). This opens the possibility that using another potentiator with a different mechanism of action could complement VX-770 activity and increase CFTR activity beyond that of VX-770 monotherapy.…”

Section: Discussionmentioning

confidence: 99%

In silicoand functional characterisation of an ultra-rareCFTRmutation identifies novel lasso motif interactions regulating channel gating

Wong

Awatade

Astore

et al. 2021

Preprint

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Characterisation of I37R – a novel mutation in the lasso motif of ABC-transporter CFTR, a chloride channel – was conducted by theratyping using CFTR potentiators which increase channel gating activity and correctors which repair protein trafficking defects. I37R-CFTR function was characterised using intestinal current measurements (ICM) in rectal biopsies, forskolin-induced swelling (FIS) in intestinal organoids and short circuit current measurements (Isc) in organoid-derived monolayers from an individual with I37R/F508del CFTR genotype. We demonstrated that the I37R-CFTR mutation results in a residual function defect amenable to treatment with potentiators and type III, but not to type I, correctors. Molecular dynamics of I37R-CFTR using an extended model of the phosphorylated, ATP-bound human CFTR identified an altered lasso motif conformation which results in an unfavourable strengthening of the interactions between the lasso motif, the regulatory (R) domain and the transmembrane domain two (TMD2). In conclusion, structural and functional characterisation of the I37R-CFTR mutation increases understanding of CFTR channel regulation and provides a potential pathway to access CFTR modulator treatments for individuals with CF caused by ultra-rare CFTR mutations.

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Clinical effects of the three CFTR potentiator treatments curcumin, genistein and ivacaftor in patients with the CFTR-S1251N gating mutation

Cited by 15 publications

References 33 publications

Breast development in a 7 year old girl with CF treated with ivacaftor: An indication for personalized dosing?

Breast development in a 7 year old girl with CF treated with ivacaftor: An indication for personalized dosing?

Molecular dynamics and functional characterization of I37R-CFTR lasso mutation provide insights into channel gating activity

In silicoand functional characterisation of an ultra-rareCFTRmutation identifies novel lasso motif interactions regulating channel gating

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