Illustration of epidermolysis bullosa airway involvement

Epidermolysis bullosa and the airway

A rare genetic disease affecting epithelial tissues

A note for patients and families: The cell and gene therapy work described on this page represents early-stage laboratory research — a proof-of-concept study. It is not yet available as a clinical treatment. We are working towards the goal of progressing these approaches to the clinic, but this will require further research and clinical trials.

Epidermolysis bullosa (EB) is a group of rare inherited disorders characterised by extreme fragility of epithelial tissues. In most people's understanding, EB is a skin condition — and skin involvement is indeed the most common presentation, with blistering and scarring occurring in response to even trivial trauma. However, EB can affect any epithelial tissue in the body, and airway involvement represents one of the most severe and least well-understood aspects of the disease.

What is epidermolysis bullosa?

EB is caused by genetic variants in genes encoding proteins that maintain the structural integrity of epithelial tissues. These proteins — including the components of laminin-332, type XVII collagen, and integrins — are essential for anchoring epithelial cells to the basement membrane, the specialised extracellular matrix that underlies all epithelial layers.

EB is classified into four main subtypes according to the level within the epithelium at which cleavage occurs: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler EB. Within these subtypes, there are at least 30 clinically distinct phenotypes, reflecting the diversity of the causative genes and variants involved. The severity of EB ranges from localised skin involvement with a near-normal life expectancy to severe, generalised disease that is associated with high infant mortality.

How does EB affect the airway?

Airway involvement is most common in two subtypes of junctional EB: JEB severe (JEB-S) and laryngo-onycho-cutaneous (LOC) syndrome. In our patient cohort within the ENT department at Great Ormond Street Hospital, both are predominantly caused by variants in LAMA3, the gene encoding the alpha-3 subunit of the laminin-332 protein complex. Laminin-332 is expressed by airway epithelial basal cells and is essential for their attachment to the basement membrane.

In the airway, loss of this adhesion leads to blistering and scarring of the fragile mucosa. This can occur spontaneously or be triggered by events such as coughing or crying. Over time, recurrent blistering and scarring cause progressive narrowing of the airway — a condition known as laryngotracheal stenosis — which can be life-threatening. Based on our experience, patients suffer high degrees of morbidity from this complication, and mortality is a real risk. Current management relies on surgical dilation and, in severe cases, tracheostomy — palliative interventions that do not address the underlying cause of the disease.

Towards a cell and gene therapy

The fundamental problem in LAMA3-associated EB is that the patient's airway basal cells cannot produce functional laminin-332. If those cells could be corrected — by restoring wild-type LAMA3 expression — and returned to the patient's airway, they might be capable of re-establishing a stable, adhesive epithelium.

We have demonstrated proof of concept for this approach using primary airway basal cells derived from children with airway EB. EB patient-derived basal cells showed weak adhesion to culture substrates consistent with their adhesion deficit, but could otherwise be expanded in culture similarly to cells from unaffected donors. Lentiviral delivery of a wild-type LAMA3 construct restored cell adhesion to levels comparable to non-EB donor cells. Corrected cells were also able to differentiate at an air–liquid interface, producing ciliated cells with normal ciliary beat frequency.

These findings support the feasibility of a combined cell and gene therapy strategy: take a small biopsy of the patient's own airway basal cells, expand them ex vivo, correct the genetic defect using a lentiviral vector, and return the corrected cells to the airway. Much work remains before such an approach could be tested in patients — but this study establishes that the key early steps are individually achievable.

Our ongoing work

At EpiCENTR, we are continuing to develop the tools needed to progress this approach towards the clinic, including scalable methods for ex vivo basal cell expansion and gene editing and optimised approaches to surgical delivery of corrected cells to the airway. This work is conducted in close collaboration with clinical colleagues at Great Ormond Street Hospital. Learn more about airway basal cells and about cell and gene therapy for airway disease more broadly.