Research achievements: Tackling the underlying cause of cystic fibrosis

There are over 2,000 different mutations of the CF gene that can cause cystic fibrosis. Some of these mutations are very common (over 90% of people with CF in the UK have at least one copy the ‘F508del’ mutation) and some of them are very rare, affecting one or two families in the UK with cystic fibrosis. We funded research in Dr Paola Vergani’s lab at UCL to develop drug screening methods for drugs that might be effective for the rarer CF mutations. Dr Vergani’s method uses light-emitting markers that show whether a would-be drug can help rescue the CF protein. Using this new method will allow speedier and more effective drug development for new CFTR modulators in the future.

Dr Mike Gray at the University of Newcastle is pursuing an alternative approaching to developing effective treatments for CF by looking to enhance the activity of proteins that work in a similar way. Conducted within a Trust-funded Strategic Research Centre (SRC) programme, Dr Gray and his international and multi-disciplinary expert team have identified a number of proteins that could be changed make the lung environment healthier for people with cystic fibrosis. They’ve been awarded a new SRC grant to look for drugs that can alter these proteins, using lab methods developed in the first SRC. If this long-term goal is successful these drugs would be suitable for anyone with CF, irrespective of their genotype.

Methods of treating CF on a genetic level  include gene therapy and gene editing. Good progress is being made towards genetic-based treatments. While these are unlikely to be available as standard to people with CF for many years, when they become available, they could make a significant difference to everyone.

Gene therapy and the UK Gene Therapy Consortium

The UK Gene Therapy Consortium (GTC)  is a group of researchers based at Imperial College London, the University of Oxford and the University of Edinburgh who are working together to develop gene therapies for cystic fibrosis. It was set up with support from the Trust in 2001. The GTC has been developing two approaches to gene therapy, a Wave 1 product using liposomes (a kind of fat) to deliver the healthy copy of the gene into the lungs, and a Wave 2 product using a viral vector as the delivery mechanism. The Wave 1 product was successful in stabilising lung disease in CF in a clinical trial. It proved the concept that gene therapy can have a beneficial effect on lung disease, and paved the way for the Wave 2 product. From 2017 onwards the GTC has been concentrating on the Wave 2 product predominately, building on the foundations of knowledge gained from the development of the Wave 1 product.

Following funding from the Trust to ensure work investigating both products could continue, in 2018 a new three-way partnership was announced where the GTC joined forces with pharma company Boehringer Ingelheim on research and development, and Oxford Biomedica on the viral delivery manufacturing for the Wave 2 gene therapy product. This collaboration will provide the substantial level of investment needed to take the Wave 2 product towards clinical trials, to establish its safety and effectiveness in humans.

The Trust has invested over £1 million in the GTC over the last five years, ensuring its work in both products could continue while searching for a major partner with the resources to take one of the products forwards.

Gene editing

A research advance published in 2012 meant that gene editing therapies may be feasible in the future. While a huge amount of research has been conducted into gene editing since then, it remains an extremely new technology. The Trust is proud to have supported early research studies into the details of how this technique may work best as a future therapy for cystic fibrosis, and this work is currently ongoing .

The effects of the malfunctioning CF protein and cycles of chronic infections can lead to permanent damage to the lungs. Currently it isn’t possible to repair lung damage that occurs in people with CF and as the lungs become more damaged a lung transplant may be required. Researchers are at the early stages of investigating an alternative to a lung transplant. Investigations of whether it is possible to replace the cells within the lungs, without needing to replace the whole organ are underway. We funded very preliminary studies to test the use of both stem cell and gene editing technologies to create cells suitable for this ‘lung graft’ approach. This area of research is now continuing within our UK Cystic Fibrosis Innovation Hub  at the University of Cambridge.