BARCELONA, Spain — For the millions of people living with genetic lung conditions, recent therapeutic advancements have improved clinical management. But for patients with cystic fibrosis (CF), who carry rare mutations, and those with primary ciliary dyskinesia (PCD), no targeted options are available. Meanwhile, next-generation delivery strategies such as viral vectors and lipid nanoparticle-mRNA platforms continue to fail against the formidable physical defensive barrier of the human airway epithelium.

At the European Respiratory Society (ERS) 2026 International Congress, Finn Hawkins, MB BCh, associate professor of medicine at the Center for Regenerative Medicine at Boston University in Boston, presented compelling preclinical evidence that transplanting airway basal stem cells could overcome these delivery hurdles, offering a durable, cell-based solution to restore tissue function in intractable respiratory diseases.

“These are some of the most exciting advances in cell-based therapies for lung diseases,” commented Sara Rolandsson Enes, PhD, an associate professor in regenerative medicine at the Lund University in Lund, Sweden, who chaired the session.

The Barrier Challenge

While targeted CF transmembrane conductance regulator (CFTR) modulator drugs have improved treatment for most people with CF, roughly 10% of patients carry rare mutations that do not respond to these medications, leaving them without effective options. For conditions like PCD, the challenge is even greater. With more than 60 causative genes and hundreds of distinct mutations affecting ciliary structure, developing individual gene therapies for each genetic variant is clinically impractical. “It’s a therapeutic nightmare,” Hawkins said. “It’s very hard to envisage a path forward.”

In addition, delivering gene-targeted therapies directly to the lower airways remains impractical. While gene-editing and mRNA delivery platforms show promise in early models, the airway epithelium is a powerful defensive shield that prevents most vectors from reaching target cells. “Over 25 viral vector trials have failed for cystic fibrosis,” said Hawkins. “In vivo gene editing is incredibly humbling in how inefficient it is in the airway.”

Instead of forcing vectors through the epithelial barrier, Hawkins’ team focused on airway basal cells — the resident stem cells positioned along the basement membrane. These versatile progenitor cells naturally regenerate the entire lung lining. By transplanting healthy basal cells, researchers can potentially treat multiple diseases. The stem cells differentiate into ciliated cells to fix clearance defects in PCD, as well as ionocytes — the primary cell type responsible for expressing CFTR — to restore salt and water balance in CF.

To demonstrate the platform’s potential, Hawkins collaborated with Alan Brown, PhD, a structural biologist at Harvard Medical School in Boston. Brown had previously identified an uncharacterized protein localized to the transition zone — the critical base of the cilium that regulates which molecules enter and exit the organelle — and predicted it played a key role in ciliary structure.

To test this hypothesis in human tissue, Hawkins’ team used CRISPR gene editing to knock out the corresponding gene, ECT2L, in human induced pluripotent stem cell (iPSC)-derived basal cells. When the engineered stem cells were differentiated into ciliated cells, electron microscopy revealed that the cilia formed bulbous, swollen tips resembling miniature tennis racquets. The researchers then screened a clinical cohort of patients with unexplained bronchiectasis and identified patients harboring variants in the exact same gene. The finding confirmed ECT2L deficiency as a newly recognized genetic cause of PCD.

Proof of Concept in Mouse Models

To evaluate whether basal cells could serve as an effective therapeutic vehicle in living tissue, Hawkins’ team turned to a concept long used in bone marrow transplantation: preconditioning.

Just as hematologists prepare the bone marrow before infusing donor cells, the researchers needed to clear the airway lining so donor stem cells could lodge and grow. They applied a mild detergent, polidocanol, to transiently strip away damaged surface epithelial cells and expose the underlying basement membrane.

The team then delivered green fluorescent protein (GFP)-labeled healthy basal cells into mice. The transplanted cells engrafted into the stripped airways, reconstituted the majority of the lining, and differentiated into functional, beating cilia that actively cleared mucus alongside recipient cells. The donor cells replenished the resident basal stem cell niche and persisted for 751 days posttransplant, which is essentially the entire natural lifespan of a laboratory mouse.

“We did not expect this result,” Hawkins said. “This was extremely exciting to us, and it motivated us to think about what the next steps are to see if this is a feasible approach.”

Next, the researchers tested whether donor cells could restore physiologic function in diseased tissue. They took healthy donor basal cells containing functional CFTR genes and transplanted them into CFTR-knockout mice — a model designed to mimic severe CF.

To evaluate whether the new cells were working, the team mounted the mice’s tracheal tissue in Ussing chambers, an electrophysiologic tool that measures transepithelial ion movement. When stimulated with forskolin to trigger channel activity, the transplanted tissue produced a sharp surge in electrical current that was subsequently blocked by a specific CFTR inhibitor. This verified that donor-derived cells had successfully engrafted and restored active chloride secretion.

“CFTR function is clearly present,” Hawkins reported. “Levels increase basically to the levels of wild-type mice, which is very unexpected and very exciting.”

Moving to Large Animal Models

To move closer to human clinical trials, Hawkins partnered with Stephen Rowe, MD, and Kadambari Vijaykumar, PhD, of The University of Alabama at Birmingham. The team tested autologous stem cell transplantation in domestic ferrets, a large animal model chosen because its lower airway anatomy and cellular composition closely mimic those of human lungs.

The researchers performed a bronchoscopic brush biopsy to harvest a few hundred basal stem cells from a ferret’s trachea. In the lab, they transduced the cells with a GFP tag for tracking and expanded them over 2 weeks into nearly 1 billion cells. They then delivered the expanded cells back into the same animal’s airway via bronchoscopy.

Initial trials yielded just 2% engraftment at 1 week posttransplant. “[It] was a remarkable result that anything worked at all,” Hawkins said. After refining their protocol, donor cell coverage surged to 65% of the tracheal surface by week 3 and reached 80% by week 6.

Biopsies at week 6 showed a fully restored, healthy pseudostratified airway lining. Single-cell RNA sequencing confirmed that the transplanted donor stem cells had successfully differentiated into all primary cell types needed for a functional lung lining, including cilia-bearing cells, mucus-secreting goblet cells, and CFTR-expressing ionocytes.

During the session’s discussion, co-chair Enes wondered how much of the airway lining must be replaced to achieve clinical benefit.

In CF, restoring 25%-50% of normal cell function is likely enough, Hawkins explained, drawing on data from drug trials and carriers who carry a single healthy gene copy. For PCD, however, the target remains unknown. It is better to have areas that are highly rescued, assumed Hawkins. “If it’s really sparse, I just imagine it’s not going to be enough.”

While autologous stem cell transplants represent the most immediate path to human trials, Hawkins envisioned a future relying on off-the-shelf, donor-derived iPSCs engineered to evade the immune system.

The primary hurdle now is developing safe preconditioning protocols for human patients, whose airways are often clogged with thick mucus and are prone to chronic infections. “Our big challenge is actually the endogenous airway epithelium — it’s so robust at regenerating,” Hawkins said, highlighting that clearing a temporary opening for donor cells without endangering the patient is essential. “It’s an entirely new field, and hopefully, I’ll have some updates for you in a few years.”

Hawkins and Enes reported no relevant financial relationships.

Manuela Callari is a freelance science journalist specializing in human and planetary health. Her work has been published in The Medical Republic, Rare Disease Advisor, New Scientist, The Guardian, MIT Technology Review, and others.