Precision Medicine for the Treatment of VEXAS Syndrome

VEXAS syndrome is a severe, systemic autoinflammatory condition, with symptoms such as bone marrow failure, fevers and thrombosis. VEXAS is caused by somatic mutations in UBA1, which encodes a crucial E1 ubiquitin enzyme. The mutations are myeloid-restricted, and UBA1 resides on the X-chromosome, so the condition predominantly affects older males.

The canonical VEXAS-causing mutations all affect a single amino acid residue in exon 3, Methionine-41 which lead to loss of cytoplasmic UBA1b, and production of an alternative, catalytically inactive, isoform called UBA1c. VEXAS syndrome is hard to treat, with no targeted therapies as yet. Allogeneic haematopoietic stem cell transplant has been shown to be curative, however due to significant co-morbidities and late age of presentations seen in VEXAS, most patients can not be considered for this option.

Therefore, more research needs to go into understanding this condition, the mutations and their impact on cellular functions, to try and identify new therapeutic targets. Our research objectives:

1. Establish robust cell culture systems to study evolution of pathogenic UBA1 mutations and their effect on cellular differentiation, molecular programme, and disease progression. 2. Determine the functional effects of newly discovered rare variants in UBA1 to select future treatment targets. 3. Detailed phenotyping of primary patient cells including platelets.