Gene Therapy & Lung Pathology

Professor Eric Alton, Group Leader

Gene Therapy

Gene therapy for cystic fibrosis (CF) The three groups in the UK undertaking clinical trials of gene therapy for CF have come together to form the UK CF Gene Therapy Consortium. The Cystic Fibrosis Trust has awarded us £15M over 5 years with the aim of negotiating with big pharma for a phase 3 clinical trial at the end of this period. Over the last year the 50 clinicians and scientists involved have undertaken the preclinical studies to select our next clinical trial candidate. This has involved developing many new assays which form the basis of core facilities placed within the three participating groups. The Consortium is milestone and product pipeline driven, and runs on principles more similar to the pharmaceutical industry than academia.

Stem cell therapy for end-stage ischemic heart disease We have brought together many of the clinicians and scientists within the RBH/NHLI interested in this field, to take forward a clinical trial of bone marrow stem cells. We are using a novel means of delivering the stem cells via a retrograde venous approach which may target large areas of the myocardium. The trial involves 46 patients, is double-blind and placebo-controlled, and has co-primary endpoints of myocardial perfusion measured by SPECT, and myocardial function measured by MRI.

Current Research Projects:

• Gene therapy for CF Following selection of the current optimal gene transfer agent, as noted above, we will move into a major clinical trial in CF patients. This will have a number of novel aspects. We will precede the trial with a one year ‘run-in’ period, during which we hope to monitor 200 CF subjects from age approximately 12 years upwards. They will be assessed 4 times during the year, with a range of assays aimed at making the link between the basic defect in CF, and the clinical phenotype that results. 100 of these patients, selected on the basis of the outcome of this ‘run-in’, will then be recruited into a 6 months, double-blind placebo-controlled trial looking, for the first time, for clinical benefit from gene therapy.
• Stem cell therapy for end-stage ischaemic heart disease We are currently undertaking pilot studies with bone marrow, to check whether the cells are viable following catheter delivery. Further, we are labelling the cells with indium¹¹¹ to allow us to check delivery into the myocardium. We have Ethics approval for the clinical trial and are beginning recruitment.

Lung Pathology

Our major focus is endobronchial biopsy in humans with studies focusing on inflammation & remodelling in the adult, child and infant and the effects of current and novel treatment in COPD & Asthma.

We also provide histological advice & support for Gene Therapy.

Our group has expertise in histology (biopsy), pathology & microanatomy, immunostaining, in situ hybridisation, high resolution scanning and electron microscopy, quantitative histological methods and image analyses and works as a central laboratory for multicentre biopsy clinical trials.

Current Research Projects:

• Mechanistic: Which are the key inflammatory cells, chemoattractants and receptors responsible for the changing character of inflammation in mild and severe exacerbations of asthma and COPD? (particular attention is paid to gene expression of neutrophils and eosinophil chemokines and receptors CXCR1, CXCR2 and cysLT1 receptor).
• Mechanistic: What are the relationships between inflammation, remodelling, symptoms and lung function deficit, as asthma develops in pre-school infants and early childhood? (A collaboration between us and University of Helsinki and with Professor Andy Bush at the RBH)
• Mechanistic: what are the pro-inflammatory mechanisms that explain the effects of experimental viral-induced infection on bronchial inflammation and mucus-hypersecretion in asthma and COPD? (a collaboration with Professor Seb Johnston)
• Hypothesis testing: Using biopsy clinical trials, what are the anti-inflammatory effects of oral PDE4 inhibition and of inhalation combination (long-acting beta agonist together with steroid) therapy in COPD?
• Exploratory: Where in the mucosa and of what type and in what number are bronchial dendritic cells? Are these altered in number in COPD or asthma and can their number be modulated by anti-inflammatory treatment? In vivo and in vitro studies.