Forskolin-induced swelling of intestinal organoids correlates with disease severity in adults with cystic fibrosis and homozygous F508del mutations

Karin M de Winter-de Groot; Gitte Berkers; Rozemarijn E P Marck-van der Wilt; Renske van der Meer; Annelotte Vonk; Johanna F Dekkers; Margot Geerdink; Sabine Michel; Evelien Kruisselbrink; Rob Vries; Hans Clevers; Frank P Vleggaar; Sjoerd G Elias; Harry G M Heijerman; Cornelis K van der Ent; Jeffrey M Beekman

doi:10.1016/j.jcf.2019.10.022

Forskolin-induced swelling of intestinal organoids correlates with disease severity in adults with cystic fibrosis and homozygous F508del mutations

Karin M de Winter-de Groot, Gitte Berkers, Rozemarijn E P Marck-van der Wilt, Renske van der Meer, Annelotte Vonk, Johanna F Dekkers, Margot Geerdink, Sabine Michel, Evelien Kruisselbrink, Rob Vries, Hans Clevers, Frank P Vleggaar, Sjoerd G Elias, Harry G M Heijerman, Cornelis K van der Ent, Jeffrey M Beekman

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

38 Citations (Scopus)

Abstract

BACKGROUND: CFTR function measurements in intestinal organoids may help to better characterise individual disease expression in F508del homozygous people. Our objective was to study correlations between CFTR function as measured with forskolin-induced swelling in rectal organoids with clinical parameters in adult patients with homozygous F508del mutations.

METHODS: Multicentre observational study. Thirty-four adults underwent rectal biopsy, pulmonary function tests (FEV1 and FVC), chest X-ray and chest CT. Body-mass index (BMI) was assessed at study visit and exacerbation rate was determined during five years prior to study visit. Organoids were cultured and measured after stimulation with 5 µm forskolin for three hours to quantitate CFTR residual function.

FINDINGS: FIS was positively correlated with FEV1 (r = 0.36, 95% CI 0.02-0.62, p = 0.04) and BMI (r = 0.42, 95% CI 0.09-0.66, p = 0.015). FIS was negatively correlated with PRAGMA-CF CT score for% of disease (r = -0.37, 95% CI -0.62- -0.03, p = 0.049). We found no significant correlation between FIS and chest radiography score for CF (r = -0.16, 95% CI -0.48-0.20, p = 0.44). We observed a trend between higher FIS and a lower mean number of exacerbations over the last 5 years of observation, but this was not statistically significant (Poisson regression, p = 0.089).

INTERPRETATION: FIS of intestinal organoids varied between subjects with homozygous F508del and correlated with pulmonary and nutritional parameters. These findings suggest that differences at low CFTR residual function may contribute to clinical heterogeneity in F508del homozygous patients and small changes in CFTR residual function might impact long-term disease expression.

Original language	English
Journal	Journal of Cystic Fibrosis
DOIs	https://doi.org/10.1016/j.jcf.2019.10.022
Publication status	E-pub ahead of print - 14 Nov 2019

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10.1016/j.jcf.2019.10.022

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de Winter-de Groot, K. M., Berkers, G., Marck-van der Wilt, R. E. P., van der Meer, R., Vonk, A., Dekkers, J. F., Geerdink, M., Michel, S., Kruisselbrink, E., Vries, R., Clevers, H., Vleggaar, F. P., Elias, S. G., Heijerman, H. G. M., van der Ent, C. K., & Beekman, J. M. (2019). Forskolin-induced swelling of intestinal organoids correlates with disease severity in adults with cystic fibrosis and homozygous F508del mutations. Journal of Cystic Fibrosis. Advance online publication. https://doi.org/10.1016/j.jcf.2019.10.022

@article{ecb689bda3e5408ca33e079b8d034e85,

title = "Forskolin-induced swelling of intestinal organoids correlates with disease severity in adults with cystic fibrosis and homozygous F508del mutations",

abstract = "BACKGROUND: CFTR function measurements in intestinal organoids may help to better characterise individual disease expression in F508del homozygous people. Our objective was to study correlations between CFTR function as measured with forskolin-induced swelling in rectal organoids with clinical parameters in adult patients with homozygous F508del mutations.METHODS: Multicentre observational study. Thirty-four adults underwent rectal biopsy, pulmonary function tests (FEV1 and FVC), chest X-ray and chest CT. Body-mass index (BMI) was assessed at study visit and exacerbation rate was determined during five years prior to study visit. Organoids were cultured and measured after stimulation with 5 µm forskolin for three hours to quantitate CFTR residual function.FINDINGS: FIS was positively correlated with FEV1 (r = 0.36, 95% CI 0.02-0.62, p = 0.04) and BMI (r = 0.42, 95% CI 0.09-0.66, p = 0.015). FIS was negatively correlated with PRAGMA-CF CT score for% of disease (r = -0.37, 95% CI -0.62- -0.03, p = 0.049). We found no significant correlation between FIS and chest radiography score for CF (r = -0.16, 95% CI -0.48-0.20, p = 0.44). We observed a trend between higher FIS and a lower mean number of exacerbations over the last 5 years of observation, but this was not statistically significant (Poisson regression, p = 0.089).INTERPRETATION: FIS of intestinal organoids varied between subjects with homozygous F508del and correlated with pulmonary and nutritional parameters. These findings suggest that differences at low CFTR residual function may contribute to clinical heterogeneity in F508del homozygous patients and small changes in CFTR residual function might impact long-term disease expression.",

author = "{de Winter-de Groot}, {Karin M} and Gitte Berkers and {Marck-van der Wilt}, {Rozemarijn E P} and {van der Meer}, Renske and Annelotte Vonk and Dekkers, {Johanna F} and Margot Geerdink and Sabine Michel and Evelien Kruisselbrink and Rob Vries and Hans Clevers and Vleggaar, {Frank P} and Elias, {Sjoerd G} and Heijerman, {Harry G M} and {van der Ent}, {Cornelis K} and Beekman, {Jeffrey M}",

note = "Copyright {\textcopyright} 2019. Published by Elsevier B.V.",

year = "2019",

month = nov,

day = "14",

doi = "10.1016/j.jcf.2019.10.022",

language = "English",

journal = "Journal of Cystic Fibrosis",

issn = "1569-1993",

publisher = "Elsevier B.V.",

}

de Winter-de Groot, KM, Berkers, G, Marck-van der Wilt, REP, van der Meer, R, Vonk, A, Dekkers, JF, Geerdink, M, Michel, S, Kruisselbrink, E, Vries, R, Clevers, H, Vleggaar, FP, Elias, SG, Heijerman, HGM, van der Ent, CK & Beekman, JM 2019, 'Forskolin-induced swelling of intestinal organoids correlates with disease severity in adults with cystic fibrosis and homozygous F508del mutations', Journal of Cystic Fibrosis. https://doi.org/10.1016/j.jcf.2019.10.022

Forskolin-induced swelling of intestinal organoids correlates with disease severity in adults with cystic fibrosis and homozygous F508del mutations. / de Winter-de Groot, Karin M; Berkers, Gitte; Marck-van der Wilt, Rozemarijn E P et al.
In: Journal of Cystic Fibrosis, 14.11.2019.

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

TY - JOUR

T1 - Forskolin-induced swelling of intestinal organoids correlates with disease severity in adults with cystic fibrosis and homozygous F508del mutations

AU - de Winter-de Groot, Karin M

AU - Berkers, Gitte

AU - Marck-van der Wilt, Rozemarijn E P

AU - van der Meer, Renske

AU - Vonk, Annelotte

AU - Dekkers, Johanna F

AU - Geerdink, Margot

AU - Michel, Sabine

AU - Kruisselbrink, Evelien

AU - Vries, Rob

AU - Clevers, Hans

AU - Vleggaar, Frank P

AU - Elias, Sjoerd G

AU - Heijerman, Harry G M

AU - van der Ent, Cornelis K

AU - Beekman, Jeffrey M

PY - 2019/11/14

Y1 - 2019/11/14

N2 - BACKGROUND: CFTR function measurements in intestinal organoids may help to better characterise individual disease expression in F508del homozygous people. Our objective was to study correlations between CFTR function as measured with forskolin-induced swelling in rectal organoids with clinical parameters in adult patients with homozygous F508del mutations.METHODS: Multicentre observational study. Thirty-four adults underwent rectal biopsy, pulmonary function tests (FEV1 and FVC), chest X-ray and chest CT. Body-mass index (BMI) was assessed at study visit and exacerbation rate was determined during five years prior to study visit. Organoids were cultured and measured after stimulation with 5 µm forskolin for three hours to quantitate CFTR residual function.FINDINGS: FIS was positively correlated with FEV1 (r = 0.36, 95% CI 0.02-0.62, p = 0.04) and BMI (r = 0.42, 95% CI 0.09-0.66, p = 0.015). FIS was negatively correlated with PRAGMA-CF CT score for% of disease (r = -0.37, 95% CI -0.62- -0.03, p = 0.049). We found no significant correlation between FIS and chest radiography score for CF (r = -0.16, 95% CI -0.48-0.20, p = 0.44). We observed a trend between higher FIS and a lower mean number of exacerbations over the last 5 years of observation, but this was not statistically significant (Poisson regression, p = 0.089).INTERPRETATION: FIS of intestinal organoids varied between subjects with homozygous F508del and correlated with pulmonary and nutritional parameters. These findings suggest that differences at low CFTR residual function may contribute to clinical heterogeneity in F508del homozygous patients and small changes in CFTR residual function might impact long-term disease expression.

AB - BACKGROUND: CFTR function measurements in intestinal organoids may help to better characterise individual disease expression in F508del homozygous people. Our objective was to study correlations between CFTR function as measured with forskolin-induced swelling in rectal organoids with clinical parameters in adult patients with homozygous F508del mutations.METHODS: Multicentre observational study. Thirty-four adults underwent rectal biopsy, pulmonary function tests (FEV1 and FVC), chest X-ray and chest CT. Body-mass index (BMI) was assessed at study visit and exacerbation rate was determined during five years prior to study visit. Organoids were cultured and measured after stimulation with 5 µm forskolin for three hours to quantitate CFTR residual function.FINDINGS: FIS was positively correlated with FEV1 (r = 0.36, 95% CI 0.02-0.62, p = 0.04) and BMI (r = 0.42, 95% CI 0.09-0.66, p = 0.015). FIS was negatively correlated with PRAGMA-CF CT score for% of disease (r = -0.37, 95% CI -0.62- -0.03, p = 0.049). We found no significant correlation between FIS and chest radiography score for CF (r = -0.16, 95% CI -0.48-0.20, p = 0.44). We observed a trend between higher FIS and a lower mean number of exacerbations over the last 5 years of observation, but this was not statistically significant (Poisson regression, p = 0.089).INTERPRETATION: FIS of intestinal organoids varied between subjects with homozygous F508del and correlated with pulmonary and nutritional parameters. These findings suggest that differences at low CFTR residual function may contribute to clinical heterogeneity in F508del homozygous patients and small changes in CFTR residual function might impact long-term disease expression.

U2 - 10.1016/j.jcf.2019.10.022

DO - 10.1016/j.jcf.2019.10.022

M3 - Article

C2 - 31735562

SN - 1569-1993

JO - Journal of Cystic Fibrosis

JF - Journal of Cystic Fibrosis

ER -

Forskolin-induced swelling of intestinal organoids correlates with disease severity in adults with cystic fibrosis and homozygous F508del mutations

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