Small Molecule Inhibitors for the Treatment of VEXAS Syndrome

Project Overview

• VEXAS syndrome carries a poor prognosis, and there are currently no treatments with curative potential aside from allogeneic hematopoietic stem cell transplantation.
• Scientists at Dana-Farber have developed a model system to study VEXAS syndrome and found that targeting the mutated gene that causes the syndrome, UBA1, selectively kills the disease-causing cells.
• Dana-Farber is interested in collaborative partners to identify and develop potentially curative compounds for VEXAS syndrome.

Technology

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a late-onset inflammatory blood disease that is associated with high mortality. The condition has an estimated prevalence of one in 4,000 males over the age of 50. The disease is caused by a mutation in UBA1, a gene involved in ubiquitination, a process that cells require to function properly. 

Roger Belizaire, MD, PhD, of the Department of Pathology at Dana-Farber, has developed a model of VEXAS syndrome that will aid in the study of disease pathogenesis and the development of effective therapies.

Current treatments for VEXAS syndrome, including steroids, hypomethylating agents, JAK inhibitors, and drugs that block inflammatory cytokines, have shown variable efficacy in controlling inflammation but rarely lead to a reduction in the number of disease-causing UBA1-mutant cells. To date, the only potential curative treatment is allogeneic hematopoietic stem cell transplantation.

To understand how UBA1 mutations cause inflammation, Belizaire and colleagues created a model system that mimics the features of VEXAS syndrome. To do so, the team inserted a copy of one of the most common UBA1 variants found in patients, UBA1^M41L, into mouse myeloid cells. As published in their Blood Advances paper in late 2023, the engineered cells containing the Uba1 mutant displayed similar pathology to VEXAS syndrome patient samples, including the overproduction of inflammatory cytokines. In addition, the VEXAS syndrome model was sensitive to killing by a small molecule targeting the UBA1 protein.

Applications

The team’s model system can be utilized to identify new cytotoxic and anti-inflammatory drugs for the treatment of  VEXAS syndrome. Additionally, it can be utilized for genetic screens to help identify novel targets that are synthetically lethal with UBA1 mutations, opening up new avenues for therapeutic development.

Opportunities

This technology is available for sponsored research opportunities to identify compounds for VEXAS syndrome treatment.

Team Members

Roger Belizaire, MD, PhD

Principal Investigator, Department of Pathology, Dana-Farber

Assistant Professor of Immunology, Harvard Medical School

Roger's Bio

Dilshad Khan, PhD

Scientist, Dana-Farber

Dilshad's Bio