Lung-targeted CRISPR therapy offers hope for cystic fibrosis

A CRISPR gene-editing therapy has the potential to offer an effective, long-lasting treatment for cystic fibrosis after overcoming a major challenge that held back previous genetic therapies.

The approach has succeeded in editing DNA in hard-to-reach lung stem cells in mice, with modifications that endured for at least 22 months – essentially the animals’ entire lives, says Daniel Siegwart at the University of Texas Southwestern Medical Center.

“I was falling out of my chair with amazement after seeing a few months of persistence,” he says. “This is exciting news for potential treatment of a variety of lung ailments.”

Cystic fibrosis is caused by genetic mutations that lead to sticky mucus building up in the lungs and digestive system.

Scientists have previously developed gene-editing technologies to modify the DNA in the faulty lung cells. But getting the therapeutic agents into those cells is a challenge due to the mucus and other defences that have evolved to keep pathogens out of the lungs, says Siegwart.

A possible solution is to deliver the molecular tools for gene editing through the blood, packaged in lipid nanoparticles that slip past immune barriers. Similar nanoparticles have already been used in more than a billion mRNA covid-19 vaccines, and other teams have successfully delivered gene therapy into people’s livers in this way.

However, lipid nanoparticles naturally end up in the liver, says Siegwart. So, a few years ago, he and his team tweaked these agents to make them specifically target the lungs.

In the latest study, Siegwart and his colleagues injected eight-week-old mice with lung-targeting lipid nanoparticles carrying CRISPR gene-editing components, together with a marker that enabled them to identify gene-edited cells. Over the next 22 months, the researchers regularly analysed the animals’ lung tissue and found the marker throughout the mice’s lungs every time.

The results were surprising, says Siegwart, because individual lung cells usually live for only three weeks at most. However, because the treatment affects the stem cells, which continually divide and produce new cells, the gene editing appears to form a replenishing pool of edited mature cells.

The researchers then ran tests in their laboratory using cells taken from people with cystic fibrosis who have a specific genetic mutation. They found that the gene-editing system embedded in the nanoparticle successfully corrected the mutation in those cells.

Finally, they injected their treatment into the veins of mice that had been genetically modified to have that same cystic fibrosis mutation. Within 10 days, the treatment had already corrected the mutation in 50 per cent of the animals’ lung stem cells.

Marianne Carlon and Mattijs Bulcaen, both at KU Leuven in Belgium, praised this new approach – which achieved what all previous efforts couldn’t. “More than 27 clinical trials for cystic fibrosis gene therapy have failed to find a way past the airway epithelial barrier,” they state in a paper commenting on the study.

“The fact that they can reach these stem cells at very high efficiency via delivery of their lung-targeted lipid nanoparticles to the bloodstream of mice is very impressive – and a first in the gene therapy field for genetic lung diseases,” Carlon tells New Scientist.

If approved for human trials, the therapy would be administered to adults and would target the lung cells only, says Siegwart. If effective, cystic fibrosis patients “could expect lung function similar to healthy adults” and the benefit would last as long as the cells themselves last, he says.

“Genome correction has the potential to generate years or perhaps a lifetime of benefit, which could dramatically improve quality of life,” he says.