Overview
|
Cystic Fibrosis
Cystic Fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, located on chromosome 7 in humans. Being an autosomal recessive genetic disease this means that for a person to develop the disease they must inherit a mutation from both parents. A person who has a mutation in only one chromosome is considered a carrier and will remain healthy. Approximately 1 in 25 people are carriers of the disease. Around 7000 people are affected by CF in the UK.
The CFTR gene encodes a protein which forms an ion channel that facilitates the movement of salt (electrically charged ions) and water across the cell membrane, from the cell cytoplasm to the extracellular space (ductal space). In CF patients, CFTR is unable to properly carry out these functions leading to dehydration of affected organs such as the sweat glands, lungs, pancreas and digestive system. As you might imagine, this phenomenon creates an environment that favours bacterial growth and consequently people who suffer from CF are susceptible to repeated respiratory tract infections which lead to inflammation and progressive lung damage. Lung disease is the primary cause of morbidity and mortality in CF.
Gene Therapy
Gene therapy is the treatment of a disease by introducing a new gene or a healthy copy of a gene into a cell. This approach is particularly pertinent to hereditary diseases where the defective gene is known. The principal aim of gene therapy is to replace or supplement a defective gene with a functional one. Although the technology is still in its infancy, it has already been used with some success in diseases such as haemophilia and cancer.
Gene therapy offers great promise for life-saving treatment for CF patients since it targets the cause of CF rather than just treating the symptoms. Gene therapy for CF had its start in 1990, when scientists demonstrated that ion conductance could be restored by giving CF cells a normal copy of the CFTR gene, but not a mutant copy. In clinical trials conducted in the late 1990s it has also been shown that CF gene therapy is safe and to some extent works in patients; however, the duration of correction was found to be short-lived and the clinical benefit of this treatment has not yet been fully realised. Importantly, these early clinical trials demonstrated the efficacy of CF gene therapy and since then steady progress has been made towards gene therapy becoming a realistic therapeutic option for the disease.
The Cystic Fibrosis Trust and the UK Cystic Fibrosis Gene Therapy Consortium
The UK Cystic Fibrosis Gene Therapy Consortium is the unified research programme of the three leading gene therapy groups in the UK. It was established in 2001 on the initiative of the UK Cystic Fibrosis Trust. The three member research groups are headed by Prof. David Porteous and Dr. Chris Boyd at the University of Edinburgh, Drs. Deborah Gill and Steve Hyde at the University of Oxford and Prof. Eric Alton, Dr. Uta Griesenbach and Dr. Jane Davies at Imperial College in London. We also have close links in Edinburgh to the Respiratory Medicine Unit at the Western General Hospital, headed by Prof. Andrew Greening and Dr. Alastair Innes; and to Dr. Steve Cunningham, consultant respiratory paediatrician at the Royal Hospital for Sick Children
The aim of the consortium is to combine the intellectual and practical expertise of the three teams and to avoid duplication of efforts thereby enhancing progress towards clinically relevant gene therapy for CF. The strengths of the consortium lie in three main areas of research: these include genetic modification of the clinical plasmid (which carries the healthy copy of the gene and regulatory genetic elements); non-viral or liposome-mediated delivery strategies; and electrophysiological assays and surrogate marker development. The Edinburgh group leads on the two main fronts of gene delivery to the lungs and marker discovery and development (see Research Projects). Due to the difficulty of measuring the function of CFTR in cells, surrogate markers are needed to indirectly measure this activity.
Generous funding from the UK Cystic Fibrosis Trust has allowed the Consortium to develop and test a lead product comprising a novel formulation of a healthy copy of the gene and a lipid-based carrier for delivery to the airways. Further tests for safety and efficiency are being carried out before a single-dose trial planned for mid-2008 and full multi-dose trials in 2009. For further information on the work of the Consortium, please see CF Today magazine, which is published by the Cystic Fibrosis Trust three times a year.
Clinical Studies
The importance of measuring CFTR expression and function in patients with CF over a period of time has been highlighted in our own work and the work of others. To this end, we completed 2 studies in 2006/2007.
The Sample Validation study assessed the reproducibility and sensitivity of our markers in human samples. The Tracking study aimed to look at simple ways of following changes in the lungs of patients with an exacerbation that didn't involve tests that were complicated or challenging for the patient. This study helped us understand how the lungs change when patients are unwell, and which markers of lung function are best at following improvements following antibiotic treatment.
We have now started a phase of pre-testing in CF patients before proceeding to gene therapy. The aim of this Run In Study is to define the level of disease activity in individual patients. This will help with selection of the most effective methods of measuring changes in the lung.
We are also in the process of designing gene therapy trials for our leading product. These trials are due to begin mid-2008.
We are very grateful to the CF Trust for funding this work, and to all the patients who have taken part in our studies already.
