ADVANCE -CFTR Development Award

Professor Nick Simmonds at the Royal Brompton Hospital is leading a research project on difficult to diagnose cystic fibrosis (CF). The title of his programme of research is Advanced Diagnostic Validation and Novel Clinical Evaluation across the CFTR spectrum, or ADVANCE-CFTR for short.

Background to the research programme

A diagnosis of CF is given based on the results of both a DNA test of the CF gene and tests of CF protein function. Sometimes it is very difficult to tell if someone has CF, especially when they have rarer CF mutations, as the tests don’t give enough information. 

Without this certainty, people affected are unlikely to get the correct treatment and their health will deteriorate. Some people wait for decades for their diagnosis to be confirmed, which causes huge distress for them and their families. 

Can mini-guts (also known as organoids) be used to help diagnose CF?

More accurate ways to test for CF are needed to give more certainty in diagnosing people with rarer CF mutations. The aim of this research study is to test the usefulness of a diagnostic method that uses mini-guts known as organoids – quite a different method in comparison to other diagnostic tests. 

As well as being able to improve certainty in CF diagnoses, the method may be able to predict whether CFTR modulator medicines such as Kaftrio could work for rarer CF mutations.

What steps are involved in the research programme?

The research programme will recruit 50 people who have been referred to the ‘Difficult to diagnose’ CF clinic that Professor Simmonds leads at the Royal Brompton Hospital in London. With their consent, the results of the usual tests conducted in the clinic will be analysed alongside the results of some additional research studies.

Building a database of difficult to diagnose symptoms and characteristics

Information about possible CF-related symptoms across different parts of the body will be stored in a secure database. This will allow the researchers to build up a picture of the prominent features, particularly if they change overtime. This includes information on lung function, sinus disease, lung infections, history of diabetes and gut symptoms and male fertility.

Several diagnostic tests will be conducted and the results will be stored alongside information on peoples’ symptoms. For example, a more detailed than usual analysis of the CF gene will be done, as well as other tests to study whether the CF protein is working or not.

Setting up organoid tests in London

Netherlands-based Professor Jeff Beekman who first developed the methods and showed the value of using mini-guts in CF research, will collaborate with researchers at King’s College and Imperial College to set up methods for collecting patient gut tissue samples, creating the organoids and testing them in the lab. This would create the first organoid testing service in the UK.

The organoids will be used to test whether or not the CF protein is working in tissue from people with difficult-to-diagnose CF. They will also be used to test whether the participants could benefit from CFTR modulator medicines. (If positive this information could be used to support a separate European / UK programme of work requesting access to modulators for these people).

Comparing all of the data to inform the next steps for research

Prof Simmonds and colleagues hope that the organoid tests will give better answers / more certainty than the existing tests on whether or not someone definitely has CF. To find out whether this is true, statisticians will analyse all of the data from the symptoms people have, the results of the hospital diagnostic tests used normally with the new tests performed in organoids.

If their results show a proof-of-concept that organoids are a useful way to improve the diagnosis of CF for people with rarer CF variants, this evidence will be used to design bigger studies in larger numbers of people.