Combined respiratory epithelial cell and gene therapy for amelioration of respiratory symptoms in children with junctional epidermolysis bullosa (Butler 1)
Completed| Project lead | Dr Colin Butler |
| Organisation | UCL Great Ormond Street Institute of Child Health, London, UK |
| Partner organizations & collaborators | Co applicants: Professor Sam Janes, Head of Respiratory Research Department at UCL, Professor Paolo De Coppi, Neonatal specialist at UCL In conjunction with: Dr Gabriela Petrof, Dr Anna Martinez, Mr Richard Hewitt (Paediatric Otolaryngologist Ear Nose and Throat GOSH) |
| Project budget | GBP 135,337.56 |
| Start date / Duration | 01. Jan 2021 / 24 months |
| Funder(s) / Co-Funder(s) | DEBRA UK, DEBRA Austria, EB MSAP/EBEP Recommended |
| Research area | Skin cancer & fibrosis, Symptom prevention & relief |
Publications related to the projects
Lentiviral expression of wild-type LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosaProject details
Short lay summary
Epidermolysis bullosa (EB) is a genetic disorder where patients suffer from extremely fragile surface tissues which painfully blister and scar with minimal trauma. It predominantly affects the external skin, however, the voicebox and windpipe can also be significantly affected. Treatment options for airway EB are very limited and often affected individuals will have difficulty swallowing and can suffer worsening breathing difficulties from airway scarring. Eventual airway blockage creates the need for a tracheostomy, a medical procedure to help open the airway. The research in this area has identified that skin grafts in the airway may provide the possibility of delivering gene-corrected airway cells to help provide a potential cure for airway disease in EB.
The gene that will be focussed on in this project is the LAMA3 gene, which is responsible for the laminin protein. This protein is important for helping cells attach to one another to provide strength to the skin and other tissues found in the airways, as well as being involved in the process of wound healing. The work here aims to discover whether a gene based therapy may help with correcting the lining of the airway that is affected by EB. Cells will be used from the airway and the LAMA gene then corrected outside of the body and reintroduced to see whether this technique will work to stop airway disease.
Scientific summary
The effects of epidermolysis bullosa (EB) in the airway are heterogenous and the full extent of airway involvement remains unknown. In patients that suffer significant morbidity and mortality as a result of epithelial disease in the larynx and trachea, the most common mutation is in the LAMA3 gene, encoding the alpha3 chain of the laminin protein. Leveraging advances in the ability to expand airway epithelial stem/progenitor cells, this proposal aims to better characterise the airway epithelium from patients with airway EB and to develop autologous LAMA3 gene-edited airway epithelial cells as a potential curative approach.
Strategic relevance
This research may also open the possibility to correct forms of EB that also affect other tissues in the body, including corneal (eye) epithelium and mucous membranes of the aerodigestive tract, (nose, lips, mouth, tongue, throat, vocal chords and upper part of the oesophagus and windpipe).
The ability to generate cell lines for airway disease in EB using this technique will also open the prospect of personalised drug testing for mass screening of small molecular compounds. This means finding a specific treatment for an individual using the data collected from this research.
What did this project achieve?
Sixteen babies with airway symptoms had genetic tests that showed thirteen of them had JEB, two had EBS and one had RDEB. A specific laminin gene (LAMA3) had genetic changes in ten of the patients, suggesting that, although the airway can be affected by other types of EB this symptom is more likely if the genetic change is in LAMA3. Genetic changes in laminin genes prevent the laminin protein from being made and cause JEB symptoms because the skin cells can’t stick down properly without it.
Airway biopsies from four of the patients were used to grow ‘airway EB’ cells in the laboratory. Researchers showed that they were missing the laminin protein made from the LAMA3 gene. Compared to cells from people without EB the ‘airway EB’ cells were less good at sticking to a cell culture dish. Gene therapy was developed to put a working LAMA3 gene into the ‘airway EB’ cells. When the cells started making protein from the new gene, they became as good as non-EB cells at sticking to the cell culture dish.
In the future, these cells would need to be grown in a way that surgeons could use them to replace the bits of damaged airway in EB patients. To confirm that this is possible, researchers practiced on a model, using 3D-printed supports to grow airway cells into grafts and transplanting them successfully.
This gene therapy requires further optimisation before it could help people with EB airway symptoms but this research shows that this sort of treatment is possible.