Gene breakthrough paves way for a cure to COPA Syndrome

SAN FRANCISCO: For over 15 years, Dr. Anthony Shum, a pulmonologist at UC San Francisco (UCSF), has sought to unravel the mysteries of COPA Syndrome—a devastating and rare genetic disorder causing severe lung hemorrhaging, kidney disease, and arthritis. While some individuals with the COPA gene mutation suffer life-threatening symptoms, others remain completely unaffected. Now, in a groundbreaking discovery, Shum and his team have identified a protective gene variant, HAQ-STING, that neutralizes the disease. This discovery could revolutionize treatment and pave the way for an effective gene therapy.

Tracing the Genetic Puzzle: How Families Helped Scientists Connect the Dots

The journey to this discovery began in 2011 when Shum treated a young woman, Letasha, for severe lung bleeding at UCSF Helen Diller Medical Center. To his surprise, her mother, Betty Towe, revealed that Letasha’s sister, Kristina, had the same condition. The sisters had been visiting UCSF for years due to their unusual combination of rheumatoid arthritis and lung hemorrhages. As Shum traced their family tree, he uncovered distant relatives in Texas and Oakland with similar symptoms.

In 2015, in collaboration with Baylor College of Medicine and Texas Children’s Hospital, Shum identified the culprit: a mutation in the COPA gene. However, only 21 of 30 family members with the mutation developed the disease. Why were some protected? The answer lay in HAQ-STING.

HAQ-STING: The Key to Unlocking a Potential Cure

The COPA gene mutation disrupts a crucial immune pathway, causing STING (a protein that fights infections) to become hyperactive, triggering chronic inflammation and tissue damage. However, some family members carried a variant known as HAQ-STING, which effectively neutralized the harmful effects of the COPA mutation.

To confirm their findings, Shum and his colleagues analyzed health records and DNA from 26 patients worldwide. They also conducted CT scans and blood tests on nine healthy relatives who carried the COPA mutation but did not develop the disease. Every healthy individual possessed the HAQ-STING variant, while none of the affected patients had it.

Gene Therapy Could Transform Lives

In laboratory tests, researchers introduced HAQ-STING into diseased lung cells. The result? The cells recovered, demonstrating that HAQ-STING could be a powerful gene therapy tool.

“This discovery opens the door to multiple treatment possibilities,” said Noa Simchoni, MD, PhD, lead author of the study published in the Journal of Experimental Medicine on February 27. “Gene therapy could be applied prenatally for infants diagnosed with the COPA mutation, or an aerosol treatment could deliver HAQ-STING directly to affected patients’ lungs.”

Hope for the Future: A Family’s Emotional Reaction

Shortly before publishing their findings, Shum called Betty to explain why she had remained healthy despite the family history. He then called Letasha and Kristina to share the breakthrough. The three women spent the afternoon in tears of joy.

“We always believed Dr. Shum would figure it out,” said Letasha. “This discovery will change lives.”

Looking Ahead

Shum and his team are now working toward clinical applications of HAQ-STING, with hopes that future patients can receive early intervention and avoid the suffering that COPA syndrome causes. This research was supported by the National Institutes of Health, the American Thoracic Society, and the Children’s Interstitial Lung Disease Foundation.