One gene variant is poised to cure a devastating inherited disease

For more than 15 years, Anthony Shum, MD, a pulmonologist at UC San Francisco, has tried to understand the random path of devastation that a rare genetic condition carves through the families it affects.

While many of those who carry the mutation develop severe lung hemorrhaging as children others never get the disease at all.

Now, Shum and a team of collaborators have found a variation in a separate gene that prevents the disease, which is called COPA Syndrome. The discovery could usher in a new gene therapy for a condition that for now can only be managed with frequent intensive care and immunosuppressant drugs.

The team found that some relatives of COPA syndrome patients remained healthy, despite having the disease-causing mutation to the COPA gene, because they also had a protective variant of another gene known as HAQ-STING. When scientists engineered the protective variant into diseased COPA lung cells, the cells got better.

"We really think HAQ-STING could be a gene therapy tool and a clear step toward a cure," said Shum, the senior author of the paper, which appears Feb. 27 in the Journal of Experimental Medicine.

The domino effect of the COPA mutation

COPA syndrome is rare, perhaps affecting a few thousand individuals in the U.S., many of whom are not diagnosed. The discovery of the COPA mutation sparked efforts worldwide to raise awareness of the disease, understand it and work toward a cure.

In 2020, while experimenting with the COPA gene in the lab, Shum discovered a second gene of interest called STING. When COPA was mutated, as is the case in people with COPA syndrome, STING went awry.

"Everybody needs STING to fight off occasional infections and get rid of viruses, but in patients with COPA syndrome, STING is on all the time," Shum said. "This causes a lot of inflammation, and for reasons that aren't totally clear, it damages the lungs, kidneys and joints."

But the researchers knew that STING had a variant, called HAQ-STING, that appeared in over a third of the population. They wondered if it might be able to neutralize the effects of the COPA mutation and explain its inconsistent effects on families.