Cell and gene therapy for airway disease
Correcting the airway epithelium through regeneration
Current treatments for most airway diseases manage symptoms or slow progression — they do not restore functional lung tissue. This limitation is particularly acute for patients with genetic diseases that disrupt the structural integrity of the airway epithelium. For these individuals, a therapy that could repair or replace the diseased epithelium at the cellular level represents a meaningful therapeutic goal.
The biological logic of airway cell therapy rests on the properties of airway basal cells — the stem cell population of the proximal airway. Basal cells can self-renew, generate all the differentiated cell types of the airway epithelium, and, crucially, can be expanded and manipulated outside the body before being returned to the patient.
The cell therapy concept
An autologous airway cell therapy approach involves taking a small biopsy of the patient's own airway epithelium, isolating and expanding the basal stem cells ex vivo, and then delivering the expanded cells to the site of disease. Because the cells are derived from the patient themselves, they do not carry the immunological risks associated with donor-derived cell therapies.
Combined with gene therapy, this concept becomes more powerful for genetic diseases. If the patient's own basal cells carry a disease-causing variant, that variant can in principle be corrected in vitro — using a viral vector to deliver a functional copy of the affected gene, or using gene editing approaches — before the corrected cells are returned to the patient. The skin epithelium has provided important precedent for this combined approach, with genetically corrected epidermal stem cells demonstrating durable engraftment and functional restoration in a small number of patients with junctional epidermolysis bullosa. Our work on epidermolysis bullosa and the airway demonstrates proof-of-concept for applying a similar strategy for airways.
The challenge of ex vivo expansion
Scalable ex vivo expansion of airway basal cells is a prerequisite for any cell therapy application. The number of cells required to cover a clinically meaningful area of diseased airway is substantial, and the biopsy material available from patients — particularly children — is limited. Over the past decade, culture methods have improved considerably, and we have recently reported a new approach using WS6 for scalable ex vivo expansion and gene editing of human basal epithelial cells that builds on this progress.
Lentiviral gene delivery
Lentiviral vectors are the most clinically advanced tool for stable gene delivery for epithelial gene therapy. They integrate into the host genome, providing durable transgene expression. The principal safety consideration for lentiviral approaches is insertional mutagenesis: integration near proto-oncogenes could, in principle, dysregulate their expression. Modern self-inactivating (SIN) lentiviral vector designs reduce this risk, and clinical experience in haematopoietic stem cell gene therapy has established a favourable safety profile in some disease contexts. Nonetheless, robust safety testing of corrected cell products before any clinical application is essential, particularly given the lack of precedent in the airway.
Delivering cells to the airway
Beyond expansion and genetic modification, a major practical challenge is delivering cells to the appropriate anatomical site in sufficient numbers, and achieving durable engraftment. The airway is a challenging delivery environment — mucociliary clearance actively removes material from the luminal surface, and the existing epithelium must be partially disrupted to allow incoming cells access to the basement membrane. The delivery of epithelial cell therapy to the airway is an active area between EpiCENTR and surgical collaborators at Great Ormond Street Hospital.
Where the field is heading
The tools available for airway epithelial cell therapy — methods for expansion, genetic modification, and delivery — are improving. Gene editing technologies including base editing and prime editing offer the potential for precise correction of pathogenic variants. Increasingly defined culture conditions are also making clinical-grade cell production more tractable. Improved understanding of the signals that govern basal cell engraftment and differentiation in vivo may identify interventions that enhance the efficiency of cell delivery. At EpiCENTR, we are working on each of these challenges, with the goal of progressing regenerative therapies for airway disease to the clinic for children affected by rare airway diseases.