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Chan Zuckerberg Initiative grant supports single-cell study of rare inherited disease

Jan. 12, 2023, 10:15 AM


by Leigh MacMillan

Alexander Bick, MD, PhD, and colleagues are studying inflammation at the single-cell level in the rare disease RUNX1-FPD.
Alexander Bick, MD, PhD, and colleagues are studying inflammation at the single-cell level in the rare disease RUNX1-FPD. (photo by Susan Urmy)

A multidisciplinary team led by Vanderbilt University Medical Center investigator Alexander Bick, MD, PhD, has been awarded a $2 million, four-year grant from the Chan Zuckerberg Initiative to study inflammation at the single-cell level in the rare disease RUNX1-FPD. The team includes the RUNX1 Research Program, a nonprofit patient organization, and investigators at St. Jude Children’s Research Hospital and Oregon Health & Science University.

“In patient-partnered research, patients and researchers work together to identify research priorities, design studies and interpret results,” said Bick, assistant professor of Medicine in the Division of Genetic Medicine. “This ensures that research is relevant to the needs of patients and addresses their concerns. It is particularly important in rare disease research as a relatively small number of patients with the rare disease are asked to contribute their time and biospecimens for study.”

RUNX1-FPD (familial platelet disorder) is caused by inherited mutations in the gene that encodes the protein called RUNX1, a master regulator of gene expression in blood-forming cells. As its name suggests, RUNX1-FPD affects platelet counts and function, and most patients suffer from bleeding issues and easy bruising. RUNX1 mutations also cause allergic and autoimmune disease and increase the risk of blood cancers.

“Beyond bleeding issues, there is significant variability in the patient experience,” said Katrin Ericson, PhD, executive director of the RUNX1 Research Program. “Some patients suffer from severe reactive airway disease; others suffer from challenging autoimmune diseases like juvenile idiopathic arthritis; and about half of patients will face a blood cancer diagnosis at some point in their life.

“Patients often experience a diagnostic odyssey before receiving genetic testing to confirm a RUNX1-FPD diagnosis, and there are no established treatments specific to the disease.”

The RUNX1 Research Program patient community continues to grow and to date includes 178 families representing 306 affected individuals.

“Our proposal came from a series of observations that RUNX1 patients made about themselves — namely that they or their children seemed to have an increased predisposition to autoimmune and inflammatory conditions long before other health problems associated with RUNX1-FPD,” Bick said.

The patients and caregivers raised questions about immune system function and inflammation through the program’s “Research Guided by Patients Committee.”

“At the RUNX1 Research Program’s annual scientific meeting, I had the unique opportunity to participate in a workshop organized by this committee where I heard firsthand from patients with RUNX1-FPD about their experiences with inflammatory diseases and questions they wanted the scientific community to answer,” Bick said. “It was a powerful reminder of how much the research we are doing matters to these patients.”

Bick and co-investigators Esther Obeng, MD, PhD, at St. Jude and Anupriya Agarwal, PhD, at the OHSU Knight Cancer Institute will explore how RUNX1 mutations contribute to inflammation using single-cell biology approaches to study gene expression programs in peripheral blood cells, bone marrow, skin and adipose tissue. They will also investigate how the different cells interact with each other.

“Peripheral blood allows us to capture circulating elements of the innate and adaptive immune system. Bone marrow, skin and adipose tissue are all accessible target tissues of inflammatory diseases,” Bick said.

Numerous anti-inflammatory medicines exist that target particular pro-inflammatory pathways, he added.

“If we identify a specific pro-inflammatory pathway that is perturbed in RUNX1-FPD, it might be possible to repurpose an existing anti-inflammatory drug for RUNX1-FPD patients.”

Bick also noted that the research findings will be widely and openly shared through the Chan Zuckerberg Initiative’s human cell atlas effort to accelerate research beyond the team’s own efforts.

“Our patient community is thrilled to be able to partner with these investigators to advance our understanding of how RUNX1 mutations drive inflammatory diseases and pave the way for treatments that can put an end to their suffering,” Ericson said.

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