Growing ‘mini-organs’ to test new CF drugs

A ground-breaking new study is testing potential new cystic fibrosis (CF) drugs on ‘mini-intestines’ grown from the cells of patients with the disease.

The international Human Individualised Treatment in CF (HIT-CF) project, led in the UK by Dr Nicholas Simmonds at Royal Brompton & Harefield NHS Foundation Trust, is currently underway and aims to help patients with rarer forms of CF. 

The first part of the project involves collecting tissue from patients with rare CF gene mutations and growing mini-intestines, known as organoids, in the lab, allowing researchers to test potential new drugs.

Where CF treatment is now

CF is one of the most common inherited diseases in Europe and is caused by a defect in the gene that is responsible for coding the CTFR protein, a protein responsible for controlling the movement of salt and water in and out of cells.

With the CTFR protein defective or reduced in people with CF, there is a build-up of sticky mucus in the lungs and digestive system, leading to breathing problems and difficulty in digesting foods. 

There are over 2000 CF-causing mutations and different mutations cause different defects in the CFTR protein, making the development of drugs for all patients extremely challenging. 

However, recent breakthroughs have been made with the development of CFTR modulator therapies; drugs that are designed to correct the faulty CFTR protein. Recent funding approval by the NHS means that soon, over 60% of patients should have access to the drugs. With newer, even more effective so-called ‘triple therapy’ on the horizon, it is predicted that 90% of people with CF will be on a modulator in the near future. 

However, that leaves approximately 10% of the CF population with rarer gene mutations being left behind because the number of individuals with these mutations is too small to run a conventional clinical trial.

That’s where organoids come in.  

What are organoids?

Organoids are microscopic sized versions of an organ grown from a few cells, that look and act similar to the organ from which they come from. It is a technique that has rapidly improved in the past decade and one the HIT-CF project is taking advantage of. 

For this study, rectal biopsies are taken from people with rare CF mutations which are then grown under laboratory conditions to produce organoids.

The organoids have the same CF mutations as the patient, allowing the researchers to screen it and see how each individual patient’s organoid responds to various new drugs.

New drug candidates from several pharmaceutical companies will be tested in the laboratory on these patient-derived organoids. 

Those patients whose organoid has a strong response to the test drugs will be given the opportunity to take part in the second stage of the HIT-CF project - a clinical trial.  

Personalised therapies

For conventional clinical trials to be effective, large numbers of patients are required to test a new treatment. For rarer diseases, and in this case rare forms of CF, this becomes impossible because there simply aren’t enough patients to test the new drugs on. 

Therefore, the second part of the HIT-CF project will involve a new way of conducting clinical trials; in effect personalising the process so that individual patients are tested with the drugs that have already been shown to have an effect on their organoids. 

This will be a ground breaking new way to conduct clinical trials.

Dr Simmonds who is leading the project in the UK says; “This is an exciting and unique opportunity to study drug responsiveness in patients with rare CF mutations with the ultimate aim of making it possible to ensure that they too have new innovative drugs in the near future to treat their CF.”

Stage 2 of the HIT-CF project is expected to begin in 2020. 

Where the study is at so far

The study aims to recruit 500 patients and is currently taking place across several CF centres in Europe that are part of the European CF Society-Clinical Trial Network (ECFS-CTN)

There are eight recruiting sites across the UK, and Dr Simmonds’ research team at the Trust has so far recruited the lion’s share of patients, with 14 patients out of the current total of 21. 

Dr Simmonds is part of the CF Clinical Trials Team and the research is being undertaken in the Trust’s Respiratory Clinical Research Facility (CRF) which has been instrumental in running the study, with Jessica Wallen as the lead research nurse. Dr Kinesh Patel, Consultant Gastroenterologist, is also a key member of the team, providing his expert skills, particularly with rectal biopsy.  

“This has been a real team effort to make this happen. I’m really grateful to the dedication and commitment to all involved, and I’d like to thank the whole team for giving these patients the opportunity to take part in this important study.” Said Dr Simmonds

To find out more about the study please visit the HIT-CF study website