Sometimes it is very difficult to tell if someone has cystic fibrosis (CF), especially when they have rare CF genes. Without this certainty, they are unlikely to get the correct treatment so their health may be affected. More accurate ways to test for CF are therefore needed in this situation. The aim of this study is to develop a more accurate test using what are called "organoids" or "mini organs." Organoids are grown in the laboratory from a small piece of gut tissue. As they have the person's exact genes, they can show if the CF gene ("CFTR") is working correctly or not and thus if the person has CF. The investigators will compare the organoid response with the current more established tests, such as the sweat test and CF genetics, and other recognised specialist tests called nasal potential difference (NPD) and intestinal current measurement (ICM). The gut tissue is usually taken by a quick, relatively painless, outpatient procedure (rectal biopsy). The additional benefit of organoids is that they can also help us to work out the best treatment for that individual by testing how well the gut tissue responds to different drugs in the laboratory. The investigators wish to carry out this research to prove that gut organoids are a better way to test for CF in this situation. The goal will be to diagnose people faster and for them to get better treatment quicker, both key for leading a longer and healthier life.
Patients with difficult-to-diagnose CF*
Adults (≥16y)
Willing to undergo rectal biopsy
Able to comply with the study
Contra-indication to rectal biopsy (e.g. significant bleeding diathesis)
History of lung transplantation
Receiving CFTR modulator treatment
Current participation (or participation within one month of enrolment) in a clinical trial of an investigational medicinal product which affects CFTR function (e.g. CFTR modulators, genetic therapies)
The investigators aim to recruit 40-50 patients from the DCFD service over a 30 month period. A formal power calculation is not possible due to the exploratory nature of the analyses. Recruitment will be opportunistic, based on estimates from the DCFD service. Up to 15 healthy (non-CFTR disease) and 15 CF controls will also be recruited to validate the tests and anchor extremes in the assays.
Cohort
Prospective
Rectal Biopsy
Procedure/SurgeryRectal biopsy sampling will be performed using either forceps or a suction device according to the method of Vonk et al (2020). Rectal biopsies will be obtained by trained and competent personnel in an appropriate setting, patients recruited will be fully informed and will have provided written consent. Once biopsy samples have been taken the resulting tissue will be processed, stored and transported using established laboratory protocols. The rectal tissue collected will be used to perform intestinal current measurements and create organoids or 'mini-organs' to allow CFTR protein function to be further characterised.
Rectal biopsy taken opportunistically during endoscopy procedure for other reasons.
Procedure/SurgeryRectal Biopsy tissue samples will be taken opportunistically for this patient cohort who are undergoing an endoscopy for other reasons. Rectal biopsies will be obtained by trained and competent personnel in an appropriate setting, patients recruited will be fully informed and will have provided written consent. The rectal tissue collected will be used to perform intestinal current measurements and create organoids or 'mini-organs' to allow CFTR protein function to be further characterised.
Blood test for CFTR Genotyping
GeneticBlood test for CFTR genotyping will be taken for Group C patients to ensure these patients are 'healthy controls' and that they do not have any CFTR gene variants associated with CF.
Quantitative assessment of CFTR function
The primary outcome is a single or composite measurement of CFTR function derived from organoid function, Sweat Chloride Concentration (SCC), Nasal Potential Difference (NPD), and Intestinal Current Measurements (ICM). These quantitative values are then used to correlate with clinical phenotype and final diagnosis, but the outcome measure itself is CFTR functional measurement across the four test modalities.
To individually phenotype patients with difficult-to-diagnose CF
To measure individual CFTR function in people with difficult-to-diagnose disease using multiple CFTR functional assays (organoids (Forskolin-induced-swelling assays and AI morphological analysis), Sweat chloride concentration, Nasal potential difference measurements and Intestinal current measurements), and to correlate this with their clinical phenotype, genotype and final diagnosis.
CFTR modulator response in intestinal organoids
To measure CFTR modulator responses of intestinal organoids derived from individuals with difficult to-diagnose disease, taken by rectal biopsy. Response will be measured using Forskolin-induced-swelling assays and AI morphological analysis.
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Royal Brompton & Harefield NHS Foundation Trust
Lead sponsor
King's College London
Collaborator
UMC Utrecht
Collaborator
Imperial College London
Collaborator
This trial is not recruiting at the moment. You can still explore other options:
