Towards cell and gene therapy for Junctional Epidermolysis Bullosa airway disease
Lay summary
There has been little research into airway symptoms in Junctional EB, limiting the therapeutic options available for children who develop airway disease. Our research at Great Ormond Street Hospital has established that variants in a particular gene – LAMA3 – are commonly associated with EB airway disease.
We aim to develop a new therapy by growing airway cells in the laboratory and adding a functional copy of the LAMA3 gene by infecting them with an (inactivated) virus. When the virus integrates into the airway cells, it allows them to make the LAMA3 protein and restores their function. Ultimately, our plan is to transplant these modified cells back to individual patients’ airways and our initial data have provided proof-of-principle that this approach works in the laboratory.
To move our approach towards clinical application, this project will develop a virus suitable for clinical use, meeting key safety and efficacy criteria. First, we will optimise our virus to produce a ‘normal’ amount of LAMA3 protein, and limit LAMA3 expression to the cell types that would normally produce LAMA3 in non-EB airways, as the effects of over- or mis-expression of LAMA3 are not known. Secondly, we will test whether this optimised approach is safe by examining cell adhesion, the ability to become other cell types, and where the virus integrates into the genome. Finally, we will use an animal model of EB to investigate whether LAMA3-corrected cells can outcompete non-corrected cells, as this will inform future surgical approaches in patients.
The primary benefit of the proposed work will be for patients with airway symptoms in EB. Often patients with LAMA3 variants have less severe skin symptoms than, for example, those with the more common LAMB3 variants, and so airway difficulties represent their primary clinical concern. For these patients, progressive airway disease and ultimately airway obstruction can become untreatable. Our proposed therapy is highly innovative and potentially curative (within the airway) for this small but clinically challenging cohort of patients.
Scientific Summary
Airway involvement in EB is rare but affected patients experience a large burden of morbidity and mortality. These patients sadly experience an inexorable scarring of the larynx in response to the normal apposition of the vocal cords in speaking and swallowing. The only available therapy for airway EB involves gentle removal of obstructing granulation tissue and dilatation and/or division of scar tissue for symptom control. Once affected, the airway mucosa is subject to further injury leading to recurrent infections due to disrupted mucociliary escalator function. Ultimately, airway stenosis ensues, with obstruction necessitating a tracheostomy. In the most severely affected patients, the trachea can also be affected, leading to more distal airway obstruction, which can become untreatable.
We propose a combined cell and gene therapy approach for airway EB. This study will develop a lentiviral vector suitable for clinical translation, while also bolstering the safety and efficacy data available for the airway cell-and-gene therapy approach. At the end of this proposal, we will be in a position to progress our approach to patients under a specials license.
We hypothesise that driving LAMA3 expression from an airway basal cell-specific promoter sequence will enable endogenous levels of expression and enable appropriate LAMA3 downregulation upon cellular differentiation.