National Heart & Lung Institute (NHLI)

Gene Therapy & Lung Pathology

  • Working in the gene therapy laboratory
  • Lentivirus transduced airway epithelial cell
  • Cells
  • Deposition scans
  • Airway epithelium
  • Airway epithelium

Professor Eric Alton, Head of Group

Gene Therapy

Gene therapy for cystic fibrosis (CF)

Human Nasal Epithelial Cells from a non-CF Subject

Human Nasal Epithelial Cells from a non-CF Subject

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 Consortium is milestone and product pipeline driven, and runs on principles more similar to the pharmaceutical industry than academia.

Since 2006 the 80 clinicians and scientists based at Imperial College London and the Universities of Edinburgh and Oxford have undertaken the following Research:

  • Preclinical Research: to find an optimal Gene Transfer Agent.
  • Sample Validation Study: looking at CF and non-CF in experimental assays.
  • The Tracking study: this involved following a CF patient during a period of lung exacerbation, whilst they were having their IV antibiotics as in-patients (or if they lived locally, at home).  We took various assays from patients during this study, the results of which showed us whether a change in the assays corresponded with any clinical improvement seen in patients.
  • The Run-in study: the purpose of this study is to assess the stability and repeatability of a wide range of tests which may be useful outcome measures in our gene therapy trials.  Over 190 patients were recruited on to this study and individuals who meet set criteria will go on to take part in the multi-dose trial. The study began in January 2008 and is due to be completed in 2012. 
  • Nasal potential difference analysis an efficacy measure of the single dose trial (Pilot study).

    Nasal potential difference analysis an efficacy measure of the single dose trial (Pilot study).

    Single Dose Trial (Pilot study): the purpose of this trial is to confirm safety of a single nebulised dose of our gene therapy; we will also look for evidence that the gene gets into the cells of the airway and works. This will rely on  laboratory tests, as it is not envisaged that after only a single dose, patients will feel any better in themselves. It is essential that we have this information before we progress further with the multi-dose trial. The trial started in February 2009.  Over 30 CF patients took part in the study which was completed in June 2011. 
  • The Multi-dose trial: we are currently looking at data to decide which 100+ patients from the run-in study will be suitable to take forward onto the mult-dose trial. The trial will be a blinded, placebo-controlled, study in which patients will receive repeat doses of either gene therapy or placebo treatment.  The multi-dose trial is due to commence in 2012.

All London patients involved in the gene therapy trial attend clinic visits at the Respiratory Clinical Research Facility at the Royal Brompton Hospital, part of the Respiratory Biomedical Research Unit.

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.

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 Bushat 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.
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