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A potential gene therapy for airway disease in Junctional EB

Grant Title: Combined respiratory epithelial cell and gene therapy for amelioration of respiratory symptoms in children with junctional epidermolysis bullosa (JEB)

Investigators: Dr. Colin Butler, Paediatric ENT Fellow / Honorary Senior Lecturer, UCL Great Ormond Street Institute of Child Health, London

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)

Institution: Great Ormond Street Institute of Child Health, London

Start Date: TBC 2020 for 2 Years

Grant amount: £135,337.56 with joint funding from DEBRA Austria

Research type: Symptom Control

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 have 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. 

The 3 main objectives of this project are to deliver laboratory-based tools to model EB airway disease, as well as to use gene editing tools to correct EB-affected airway lining.:

Objective 1: Understand in greater depth more about the epithelium (tissues) that are affected in the airways in junctional EB;

Objective 2: Generation of potential methods for LAMA3 gene correction using viral vectors, (viruses used as a way to deliver the corrected gene); 

Objective 3: Test to see how the LAMA3 gene-corrected treatment is received in a living model.

These overall aims are to help provide pilot or preliminary data towards gene edited therapies for EB airway disease and also generate a rare resource of primary cell lines, (specialised cells to advance scientific understanding), for the development of personalised medicine strategies.

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.

About this research and why it is important:
"EB affecting the airway is a rare phenomenon but for those affected the condition leads to severe breathing problems because of the scarring. Those affected have breathing tubes that are so small that it would be similar to breathing through a straw. Clinical options are severely limited with the only way addressing a narrowing airway is to dilate the airway with a balloon. Whilst dilation can help alleviate the immediate narrowing, the additional trauma leads to further scarring. This research aims to understand this process and develop ways in treating it, particularly by developing novel ways of growing specialised skin for the airway. The hope is that by tackling the airway, other areas can be targeted using similar techniques. Being able to treat scarring of the airway with implantable airway mucosa that are made from a patient’s own cells would really change the way we can treat this disease”

Dr Colin Butler

Investigator Biography:

Colin Butler is an Ear Nose Throat Clinician Scientist at Great Ormond Street Hospital and has a specialist interest in treating children with significant airway problems. He has undertaken a surgical fellowship in this area and has experience in transplanting skin into the airway. He is now part of a team treating children who have EB affecting their airway. His PhD has been in regenerative medicine and was awarded a Wellcome fellowship investigating way to expand adult airway stem cells towards epithelial therapies for the airway. He has published extensively in the airway field and has had experience in developing products from ‘bench to bedside’.