Organoid Study R334W
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|ClinicalTrials.gov Identifier: NCT04254705|
Recruitment Status : Not yet recruiting
First Posted : February 5, 2020
Last Update Posted : February 5, 2020
|Condition or disease||Intervention/treatment||Phase|
|Cystic Fibrosis||Procedure: Rectal Biopsy||Not Applicable|
Rationale: CF is caused by mutations in the 'Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)' channel that codes for the CFTR protein, an anion channel. More than 2000 different CFTR mutations have been described. CFTR modulator drugs treat the underlying protein defect by improving folding and trafficking of nascent protein (corrector) or by improving channel opening at the cell membrane (potentiator). In the European Union, treatment with CFTR modulators has only been approved for patients who are homozygous for F508del or carry a mutation of class III or one of a limited number of residual function mutations.
The R334W-CFTR mutation is a rare mutation (270 subjects in the European CF Registry ECFSPR), described in CFTR2 as disease causing. Clinically there is evidence for residual CFTR function in these subjects since only 36% of the patients with R334W are pancreatic insufficient and the mean age of all patients in the CFTR2 database is a bit older (22 years) than patients with CF and 2 known disease causing mutations (20 years). On the other hand, patients with R334W have on average a high sweat chloride (mean 95 mmol/L) and severe lung disease; their mean FEV1 reported to the CFTR database  is very similar to that of other patients with the F508del CF causing mutation. In the Leuven clinic we have one subject with R334W/F508del who is 60 year old and has very severe lung disease (FEV1 in the low 40s).
When studied in FRT (Fisher rat thyroid) cells and compared to wild type, the R334W mutation is reported to give rise to normal levels of protein at the cell membrane, but very much decreased function (short circuit current measurement) of 1.3% of wild type. On the other hand there is very limited rescue of CFTR function after addition of the potentiator ivacaftor: from 1% to 5 % of normal.
In contrast with expression in heterologous systems, intestinal organoids allow study of CFTR function in patient specific material. When tested in intestinal organoids from the patient with F508del/R334W in the Leuven clinic, this mutation resulted in some residual function documented by forskolin induced swelling at higher forskolin concentrations, even before addition of CFTR potentiator or corrector. However, addition of ivacaftor and to a lesser degree lumacaftor results in moderate to good rescue of function; the degree of rescue (FIS result) is intermediate between that seen in F508del homozygous subjects and class III mutation subjects. Comparable results are obtained in prof M Amaral's lab in 3 subjects compound heterozygous for F508del/R334W (results in nasal cells, and intestinal organoids). A CFTR functional rescue in organoids from a subject with the R334W/R746X is also reported by the Dutch Utrecht group in organoids; the forskolin induced swelling induced by luma/iva was again between the response seen with iva in organoids from subjects with gating mutations and by luma/iva in organoids derived from F508del homozygous subjects. These findings suggest that R334W might be a suitable candidate for TEZ/IVA treatment.
The study described in this protocol will be the first step of a larger project that also includes a clinical trial. With the present study, the response of organoids of patients with mutation R334W to available
CFTR-modulators will be tested to identify the in vitro response. An interventional clinical trial, submitted as a separate protocol, will subsequently assess the response to modulators in vivo in the same patients. The clinical trial is thus not part of this protocol.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||30 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||For stratification of subjects in the subsequent clinical trial|
|Masking:||None (Open Label)|
|Official Title:||Response to CFTR-modulators in Intestinal Organoids of Patients With CF Having at Least One R334W Mutation|
|Estimated Study Start Date :||March 1, 2020|
|Estimated Primary Completion Date :||September 1, 2020|
|Estimated Study Completion Date :||March 1, 2021|
Subjects with CF and R334W mutation
Subjects with CF and R334W mutation
Procedure: Rectal Biopsy
Suction biopsy or forceps biopsy
- Response to CFTR-modulator in Intestinal Organoids: Increase in Forskolin induced swelling by addition of tezacaftor+ivacaftor after stimulation with Forskolin (0.8 µmol/L) [ Time Frame: At study completion (when rectal biopsy is performed or when organoids are retrieved from the biobank and FIS has been performed), an average of 2 months ]Response to tezacaftor+ivacaftor in the Forskolin Induced Swelling (FIS) assay in rectal organoids
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04254705
|Contact: François Vermeulen, MD PhD||+32 16 34 06 49 ext +3216343599||François.Vermeulen@uzleuven.be|
|Contact: Els Aertgeerts||+32 16 34 38 31 ext +3216343599||Els.Aertgeerts@uzleuven.be|
|University Hospital of Leuven|
|Centre Hospitalier Lyon Sud|
|Centre Hospitalier Régional Universitaire Montpellier|
|Instituto G. Gaslini|
|Fondazione Ospedale Maggiore Policlinico|
|Ospedale Pediatrico Bambino Gesù|
|Sapienza university - Centra Fibrosi Cistica Regione Lazio|
|Azieda Ospedaliera Universitaria Integrata|
|Hospital Santa Maria|
|Hospital Universitari Vall d'Hebron|
|Principal Investigator:||François Vermeulen, MD PhD||Universitaire Ziekenhuizen Leuven|