Game-changing breakthroughs in Cystic Fibrosis treatment

Dr Chris Boyd, Institute of Genetics and Cancer

Can you explain in lay terms what cystic fibrosis is and how many people it affects?

Cystic fibrosis (CF) is a life-limiting genetic disease affecting people inheriting bad mutations (DNA mistakes) in both copies of a gene called CFTR. Their cells cannot produce normal CFTR protein which is needed to make sure that organs such as the gut, pancreas, reproductive system and – most importantly – the lungs work efficiently. As a result, the sticky mucus in inherently inflamed lungs of people with CF allows harmful germs to gain a foothold leading to frequent infections which cause cumulative lung damage. Without treatment (such as lung transplants), the most common cause of death from CF is respiratory failure. Over 160,000 people worldwide have CF and one in every 2,500 babies are born with the disease. In the UK, there are about 10,000 people with CF, of whom 900 live in Scotland.

What is the UK Respiratory Gene Therapy Consortium, when was it formed and why?

The UK Respiratory Gene Therapy Consortium (GTC) was formed in 2001 with the aim of developing gene-based treatments for CF, and more recently other lung diseases. In the 1990s, most UK clinical-level CF gene therapy research was carried out in groups from the Universities of Edinburgh, Oxford and Imperial College London.

Each group had demonstrated clinically the proof-of-concept that normal CFTR genes, delivered by spraying DNA onto nostril cells in people with CF, started making the normal CFTR protein. The principle of gene therapy is that delivering a normal version of a faulty disease gene to cells in affected people will partially or fully alleviate their disease. For CF gene therapy, the three groups coated copies of the normal CFTR gene in a synthetic material to create a composite product (or vector) designed to be taken up by lung cells and deliver the gene.

Uniting these research groups in a Consortium to pursue the common goal enabled it to avoid duplication and leverage economies of scale to accelerate gene therapeutic development from bench to bedside. With substantial support from the UK CF Trust, the newly-formed GTC set about optimising the normal CFTR gene copy to make it less toxic, and worked out the best way of preparing and delivering the vector into lungs through a nebuliser.

In 2012-2014, these efforts culminated in a two-centre clinical trial of our non-viral gene therapy vector in a total of 130 people with CF in Edinburgh (Western General and Sick Kids’ hospitals) and London. We showed for the first time that CFTR vector treatment was able to stabilise lung function in the treated subjects.

However, the GTC’s aim was to improve lung function through gene therapy. Thus, we prioritised development of a virus-based CFTR vector which was much better at delivering genes to lung cells. The GTC soon formed a partnership with two companies, Boehringer Ingelheim (BI) and Oxford Biomedica (OBM), to accelerate pre-clinical development. In 2021, BI took up the option to develop the vector for clinical studies and at the end of 2024, started a clinical trial to test the viral CFTR vector pioneered by the GTC, with the results to be announced in due course.

What is your role in the consortium?

Since 2002 I have been a member of the GTC’s Strategy Group, which comprises seven senior scientists from the three collaborating Universities, chaired by Professor Eric Alton at Imperial. All members contribute collectively to shaping the clinical goals and experimental programme of the GTC, but we each have particular skills to offer: mine include the design of therapeutic genes and assessing the toxic and other effects of using viruses to deliver genes to human lung cells. We meet online at least once every week.

How has treatment of CF improved and what have been the biggest breakthroughs in recent years?

The game-changing breakthrough in CF treatment in the last 20 years has been the development of potent small molecule drugs called modulators, which when taken in pill form treat the root cause of the disease at the CFTR protein level. Previously established drugs, such as antibiotics and digestive supplements, only treat the symptoms – while capable of increasing life expectancy, they can only reduce the rate of lung deterioration. Modulators, however, improve lung function and the lung’s ability to clear inhaled bacteria before infection sets in. The signs are that those who respond well to modulators will enjoy better health and significantly extended lifespans.

Why is gene therapy still being developed for CF?

Despite the success of modulator therapies, 10-15% of people with CF are unable, for genetic and other reasons, to benefit. This represents a substantial unmet need for which gene therapy is an ideal solution: because of the way CF gene therapy works, it can in principle treat anyone in the 10-15% category. A large number of different gene therapeutic approaches are being studied around the world in attempting to achieve this goal, and we are proud that the current BI-sponsored trial using a viral CFTR vector derived from the one pioneered by the GTC is a significant component of the worldwide effort aiming to ensure that no one with CF is left behind. The GTC’s work was only possible through the generous funding and other support from the host Universities, research councils, charities and people with CF.