Correction of CFTR function in intestinal organoids to guide treatment of Cystic Fibrosis

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064203%3A_____%2F21%3A10413224" target="_blank" >RIV/00064203:_____/21:10413224 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11130/21:10413224

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=~S-QCkd87" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=~S-QCkd87</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1183/13993003.02426-2019" target="_blank" >10.1183/13993003.02426-2019</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Correction of CFTR function in intestinal organoids to guide treatment of Cystic Fibrosis

Popis výsledku v původním jazyce

RATIONALE: Given the vast number of CFTR mutations, biomarkers predicting benefit from CFTR modulator therapies are needed for subjects with cystic fibrosis (CF). OBJECTIVES: To study CFTR function in organoids of subjects with common and rare CFTR mutations and evaluate correlations between CFTR function and clinical data. METHODS: Intestinal 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 RESULTS: Across 28 genotypes, residual CFTR function correlated tightly (r(2)=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 (r(2)=0.90) and sweat chloride (r(2)=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. CONCLUSIONS: Measurements 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.

Název v anglickém jazyce

Correction of CFTR function in intestinal organoids to guide treatment of Cystic Fibrosis

Popis výsledku anglicky

RATIONALE: Given the vast number of CFTR mutations, biomarkers predicting benefit from CFTR modulator therapies are needed for subjects with cystic fibrosis (CF). OBJECTIVES: To study CFTR function in organoids of subjects with common and rare CFTR mutations and evaluate correlations between CFTR function and clinical data. METHODS: Intestinal 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 RESULTS: Across 28 genotypes, residual CFTR function correlated tightly (r(2)=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 (r(2)=0.90) and sweat chloride (r(2)=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. CONCLUSIONS: Measurements 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30203 - Respiratory systems

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

European Respiratory Journal

ISSN

0903-1936

e-ISSN

—

Svazek periodika

57

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

13

Strana od-do

1902426

Kód UT WoS článku

000608406300013

EID výsledku v databázi Scopus

2-s2.0-85096085320