Genome editing of lung stem cells treats cystic fibrosis in mice

A CRISPR genome-editing therapy has been shown for the first time to provide long-term genome correction in lung cells for treatment of cystic fibrosis in mice.

Lung-selective lipid nanoparticles (LNPs) were used to deliver a CRISPR genome-editing therapy specifically to lung cells in a mouse model of cystic fibrosis. A study published in Science showed that this genome-editing approach persisted for at least 22 months across all lung cell types. The LNP-mediated CRISPR therapy achieved 50 percent genome correction at a common cystic fibrosis mutation, R553X, in mice and restored the function of the cystic fibrosis transmembrane conductance regulator (CFTR) by 53.4 percent in human bronchial epithelial cells derived from patients with cystic fibrosis.

'Scientists have previously shown that genome editing in the liver is durable, but it was unknown whether the lungs had this capacity. Here, we discovered that lung-targeting lipid nanoparticles can deliver gene correction technologies to lung stem cells, which then differentiate into a healthy epithelium,' Dr Daniel Siegwart, who led the study at the University of Texas Southwestern Medical Centre in Dallas, said.

Cystic fibrosis is a disease caused by a range of genetic mutations in the CFTR gene, leading to the production of a defective channel in lung endothelial cells. This defect results in the accumulation of sticky mucus in the lungs and digestive systems.

Numerous barriers have historically hindered the delivery of gene therapies to lung cells. These challenges include physical obstacles such as mucus, the degradation of genome editors during delivery, and the difficulty of targeting lung stem cells.

Targeting other lung cell types (which mature from resident stem cells) does not produce long-term efficacy due to their high turnover rate and lifespans ranging from a few days to several weeks.

Researchers discovered that by coating the LNPs in a blood plasma protein vitronectin, they enabled the therapy to be specifically delivered to lung cells – most of which express the vitronectin receptor, thereby facilitating binding and cellular uptake.

The researchers encapsulated base editors in LNPs and injected the therapy into the veins of mice with the R553X mutation. After ten days, researchers analysed the lung tissue and found 50 percent of the lung stem cells were corrected to a regular sequence at the mutated site.

They went on to confirm the success of this approach in human bronchial epithelial cells derived from patients with cystic fibrosis, where they showed function was restored to 53.4 percent. This was further enhanced to 85 percent when used in combination with Trikafta, the current leading cystic fibrosis treatment.

'[It's] a first in the gene therapy field for genetic lung diseases,' said Dr Marianne Carlon, researcher in the Laboratory of Respiratory Thoracic Surgery (BREATHE) at KU Leven, Belgium, who was not involved in the research but co-wrote an accompanying related perspective in Science.

After 27 failed clinical trials for cystic fibrosis gene therapy, this study demonstrates the potential of genome-editing in lung cells to provide a durable therapy for cystic fibrosis and other genetic lung diseases. The next steps would be to investigate the translatability of the genome-editing therapy to humans.