For more than 15 years, anthony shum, md, a pulmonologist at uc san francisco, has tried to undersrstand the random path of devastation that a rare genetic condition carves through the family.

While many of that who carry the mutation development development 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 preventes 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 immuppressant drugs.

The team found that some relatives of copa syndrome patients remained 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 in the Journal of Experimental Medicine,

Families and Clinicians Connect the dots

In 2011, Shum was called in to help stabilize a patient in the emergency room at the ucsf helen diller medical center. The patient, a young woman named Letasha, Had Severe Bleeding in the Lungs. It wasn’t clear what was causing letasha’s condition. But shum began to suspect it has a genetic cause when the woman’s mother, betty towe, told Him Her Other DAUGHTER, Kristina, Had Nearly Identical Symptoms.

Since Early Childhood, Both Letasha and Kristina Had Routinely Visited UCSF to be treated for their unusual combination of life-threatening bleeding in the lungs and rheumatoid arthritis. Betty Always Accompanied Her Daughters on the Four-Hour Trip From Oakdale, California to UCSF.

Shum began helping them navigate care at ucsf while investing how far these symptoms extended through his family trees. He soon became their primary pulmonologist.

“My Mom’s Cousin Mentioned That We had distant relatives in texas, third courses, who had a young Daughter with Lung Problems and Arthritis, Ander Relatives in Oak Similland with Simillar Problems,” Letasha, who is now 43. “Dr. Shum Took Blood Samples from all of us and start to connect the dots.”

In 2015, Shum, Along With Colleagues from Baylor College of Medicine and Texas Children’s Hospital, Announced that they had found a common factor behind these symptoms in five failies: a mutation Copa. While 30 Individuals Across these Families Had the Mutation, only 21 of them was stricken by the disease, which they dubbed copa syndrome.

The domino effect of the copa mutation

COPA Syndrome is Rare, Perhaps Affecting a Few Thought Individuals in the Us, 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 Cope 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 are totally clear, it damages the lungs, kidneys and joins.”

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 familys on. To test their hypothesis, they’D need the cooperation of dozens of patients –nd their healthy family members.

Letasha, Kristina and Betty Immedited Stepped Up.

“Whenever Dr. Shum has asked us to help with his research, I was so happy to do all of it – Donating, Working with Them, Taking Any Tests,” Letasha Said. “I knew he would figure it out.”

Shum joined forces with another baylor college of medicine pediatrician, tiphanie vogel, md, ph.d., and others to assemble health records and DNA Samples from 26 Patients with Copa Syndrome forms Around the world.

They also put nine healthy relatives with the copa mutation through several rounds of testing, including ct scans and blood tests for information, to make sure they did not have any symptoms of the day. Then, the team sequenced the sting gene in every patient and relative.

“All the Healthy Relatives Had Haq-Sting, While None of the COPA Syndrome Patients Had it,” said noa simchoni, MD, Ph.D.D., APUNOLOGIST at UCSF who is the first author of the paper. “It’s the first report of a common allele providing total protection from a severe genetic disorder.”

Haq-Sting Clears a Path to a Cure

Simchoni and Shum Saw a clear Opportunity to Test Whether Haq-Sting Goods BE Used Therapeutically. They took lung cells from a patient with copa syndrome and treated them with haq-sting, akin to gene the therapy in a petri dish. Even thought these cells alredy had other forms of sting, the addition of Haq-Sting BRURUGHT their Immune Signals Back into Balance.

Shum Sees Several Promising Paths for Turning the Haq-Sting Discovery Into Relief for Cope Syndrome Patients.

“Maybe if a baby is diagnosed prenatally with the copa mutation, but lacques haq-sting, we cold do prenatal genealypy,” said shum, noting how ucsf’s tippi mackeenzie, mackeenzie, mdonstratede Can work. “Or in adults, we could deliver haq-sting in an aerosol directly to their airways and protect their lungs.”

A less weeks before the discovery was to be published, Shum Gave Betty a call to share the news. He explained that she had remained healthy through her 60-plus years, accuse Haq-sting had protected her. Then Shum Called Letasha and Kristina.

The mystery of their family’s health has been solved. Maybe, in the future, others would also be spared from the suffering the Had Endured.

“We’ve Always Believed Dr. Shum Bold Get to the Bottom of It,” Letasha Said. “I hope he undersrstands the amazing things. It’s going to change people’s lives.”