1 gene variant is poised to cure a devastating inherited disease

(Press-News.org) 1 Gene Variant Is Poised to Cure a Devastating Inherited Disease
Scientists compared five families and multiple generations to find a gene variant that prevents COPA Syndrome and opens the door to a new gene therapy for the condition.

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.  

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 had 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 investigating how far these symptoms extended through their family tree. He soon became their primary pulmonologist. 

“My mom’s cousin mentioned that we had distant relatives in Texas, third cousins, who had a young daughter with lung problems and arthritis, and other relatives in Oakland with similar problems,” said Letasha, who is now 43. “Dr. Shum took blood samples from all of us and started 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 families: a mutation in a gene called COPA. While 30 individuals across these families had the mutation, only 21 of them were stricken by the disease, which they dubbed COPA syndrome. 

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. To test their hypothesis, they’d need the cooperation of dozens of patients – and their healthy family members. 

Letasha, Kristina and Betty immediately 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, PhD, and others to assemble health records and DNA samples from 26 patients with COPA syndrome from 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 inflammation, to make sure they did not have any symptoms of the disease. 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, PhD, a pulmonologist 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 could be used therapeutically. They took lung cells from a patient with COPA syndrome and treated them with HAQ-STING, akin to gene therapy in a petri dish. Even though these cells already had other forms of STING, the addition of HAQ-STING brought their immune signals back into balance.  

Shum sees several promising paths for turning the HAQ-STING discovery into relief for COPA syndrome patients. 

“Maybe if a baby is diagnosed prenatally with the COPA mutation, but lacks HAQ-STING, we could do prenatal gene therapy,” Shum mused, noting how UCSF’s Tippi MacKenzie, MD, has already demonstrated how this can work. “Or in adults, we could deliver HAQ-STING in an aerosol directly to their airways and protect their lungs.” 

Discovery brings understanding and hope 

A few 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 because HAQ-STING had protected her. Then Shum called Letasha and Kristina. 

Soon the three women were calling each other, crying tears of joy all afternoon. The mystery of their family’s health had been solved. Maybe, in the future, others would also be spared from the suffering the had endured. 

“We've always believed Dr. Shum would get to the bottom of it,” Letasha said. “I hope he understands the amazing thing he's doing. It’s going to change people’s lives.” 
 
Authors: Other authors are Christopher S. Law, Brett Elicker, MD, and Santosh Kurra, PhD (UCSF); Senkottuvelan Kadirvel, PhD, Bo Yuan, PhD (Baylor College of Medicine); Shogo Koide, Yoshihiko Kuchitsu, PhD, Tomohiko Taguchi, PhD, (Tohoku University in Japan); Maryel Likhite, Margaret Mei-Kay Wong, MS, David B. Beck, MD (NYU); Alice Grossi, PhD, Stefano Volpi, MD, PhD (Gaslini Institute in Italy); Ronald M. Laxer, MD, Dilan Dissanayake, MD, PhD (Hospital for Sick Children in Canada). 

Funding:This work was supported by the National Institutes of Health (R21AI160107, R01AI168299, T32AR007304, F32HL172586), the American Thoracic Society, and the Children’s Interstitial Lung Disease Foundation.  

About UCSF: The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. UCSF Health, which serves as UCSF's primary academic medical center, includes top-ranked specialty hospitals and other clinical programs, and has affiliations throughout the Bay Area. UCSF School of Medicine also has a regional campus in Fresno. Learn more at ucsf.edu, or see our Fact Sheet.

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