Lung cell discovery opens new route for cystic fibrosis treatment

Scientists already know cystic fibrosis is caused by mutations in the gene they call cystic fibrosis transmembrane conductance regulator (CFTR), but they didn’t know where expression of the gene is active in the body. Using novel sequencing technologies, two separate teams have now discovered a rare cell type in airway tissue that appears to play a key role in the genetic disorder.

The teams—one led by scientists at the Novartis Institutes for BioMedical Research (NIBR) and Harvard Medical School, the other by researchers at the Broad Institute and Massachusetts General Hospital (MGH)—have each described their findings in Nature and named the new type of cell “pulmonary ionocyte.”

Both teams used an emerging technology called single-cell RNA sequencing to profile cells in airway tissue. That allowed them analyze thousands of cells and to determine which genes were active in each cell.  The Broad team used the information to create an “atlas” that maps the location of each cell type.

One cell type that didn’t look like anything previously described in scientific literature popped out. The cell only makes up about 1% of the cell population in mice and humans and resembles ionocytes—cells that transport ions and are most commonly found in fish and frogs. In fish, ionocytes help maintain an equilibrium with the water. In mice and humans, this newly discovered cell moves ions at the interface between tissues and the surrounding air.

The Novartis-Harvard team embarked on a similar effort to catalog lung cells and made the same ionocyte discovery. “When each group became aware of the other’s work, we agreed that giving the new cell type the same name and publishing together would reinforce the findings,” Aron Jaffe, a corresponding author of the Novartis-Harvard study and a co-leader of respiratory disease research at NIBR, told FierceBiotechResearch.

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As it turned out, these ionocytes express the gene CFTR at high levels, according to the teams. The Broad-MGH researchers disrupted a critical molecular process in pulmonary ionocytes in mice, and observed symptoms key to cystic fibrosis, including the formation of dense mucus. They were surprised by their findings because the dominant hypothesis proposes that CFTR is expressed in ciliated cells, a common respiratory cell type that has hair-like structures on its surface to sweep away mucus, dust and bacteria. 

Both teams recognize that their discovery could enhance future cystic fibrosis therapies. Vertex currently has several approved CF therapies, Kalydeco, Orkambi and Symdeko, that are designed to correct the dysfunctional or lack of protein caused by mutated CFTR gene. But they don't directly target the rogue gene.

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“Knowing where CFTR is active provides a crucial piece of information to help guide potential new therapeutic approaches, including the possibility of developing gene therapy for cystic fibrosis,” said Jaffe. Because a gene therapy that corrects for a mutation in CFTR would need to be delivered to the right cells, the newly created atlas could be key to its development, the Broad-MGH scientists figure.

Besides cystic fibrosis, the Broad-MGH team also located other disease-associated genes that are expressed in the airway. In one case, the researchers found that a gene linked to asthma is expressed by ciliated cells.