Development of UBA1 Targeted Therapies in VEXAS Syndrome

Building a fluorescence-based cellular screening platform to identify small molecules targeting mutant UBA1, this project addresses an acute unmet need in VEXAS syndrome and lays groundwork for broader rheumatic disease therapies.
Complete Autoinflammatory Diseases Cross-Cutting & Special Populations Rare Autoimmune Diseases Animal Models Biological & Mechanistic Drug Repurposing Experimental Platforms & Models Human Genetics In Vitro Models Innate Immunity Therapeutic Development Translational & Clinical

Funding Year: 2023

Project Overview

VEXAS syndrome is a severe autoinflammatory disease caused by somatic, loss-of-function mutations in UBA1 — a gene restricted to the hematopoietic system — resulting in reduced global ubiquitylation and serious rheumatic and hematologic manifestations. Currently, no effective targeted treatments exist. This project developed a robust fluorometric cellular assay using a CHO (Chinese hamster ovary) cell line carrying a temperature-sensitive UBA1 mutation to screen for small molecule compounds capable of either rescuing or selectively inhibiting mutant UBA1 activity. The resulting assay platform is designed to support unbiased drug screens, with lead compounds to be validated in established in vitro and animal models.

Impact & Innovation

The first targeted therapy within reach for VEXAS

 

This project established a screening platform to identify mutant UBA1–targeting compounds — and characterized a novel molecule inducing selective lethality in VEXAS mutant cells, a first step toward effective therapy.

  • Addresses a critical therapeutic gap in VEXAS syndrome, a severe autoinflammatory condition with no approved targeted treatments
  • Confirmed three key results — a robust UBA1 activity assay, mutation testing, and a novel inhibitory molecule — catalyzing NIH R01 R01AR083407
  • Advances the Consortium’s From Mechanistic Insight to Translation pillar, bridging molecular discovery to therapeutic development in a disease with no current targeted treatments
RESEARCH APPROACH

A framework designed for discovery

This project combined cellular assay development with small molecule screening to identify and characterize UBA1-targeted therapeutic candidates for VEXAS syndrome. The work moved from assay construction and validation through compound testing and early mechanistic characterization.

Development of a fluorometric, cell-based assay using a CHO cell line carrying a temperature-sensitive UBA1 mutation, followed by small molecule screening to identify compounds that rescue or selectively inhibit mutant UBA1 activity, with downstream validation in in vitro and animal models.

CHO cell line with temperature-sensitive UBA1 mutation (ts20), fluorescence-based UBA1 activity readouts, putative mutation testing panels, and established in vitro and preclinical animal models for lead compound validation.

Identification and characterization of lead small molecule compounds targeting mutant UBA1, with selective lethality in VEXAS-mutant cells. Findings are intended to advance toward preclinical validation and inform therapeutic development for VEXAS syndrome and related rheumatic and hematologic diseases.

INVESTIGATORS & INSTITUTIONS

Powering the science

Principal Investigator

David B. Beck, MD, PhD, Associate Director, Judith & Stewart Colton Center for Autoimmunity (NYU)

Department of Medicine (Rheumatology), NYU Grossman School of Medicine / NYU Langone Health, New York University

Colton Centers & Institutions

Judith & Stewart Colton Center for Autoimmunity at NYU Langone Health

NYU Grossman School of Medicine

RESEARCH OUTPUTS

From insight to impact

Publications

Skin manifestations of VEXAS syndrome and associated genotypes

JAMA Dermatology
Tan, IJ; Ferrada, MA; Ahmad, S; Fike, A; Quinn, KA; Groarke, EM; Beck, DB; Allbritton, J; Castelo-Soccio, L; Young, NS; Patel, BA; Grayson, PC; Cowen, EW June 2024
Biological & MechanisticBiomarker DiscoveryDisease SubtypingExperimental Platforms & ModelsHuman CohortsHuman GeneticsInnate ImmunityTranslational & ClinicalAutoinflammatory DiseasesCross-Cutting & Special PopulationsDermatologic DiseasesRare Autoimmune DiseasesNew York University

Description of a novel splice site variant in UBA1 gene causing VEXAS syndrome

Rheumatology
Ospina Cardona, D; Rodriguez-Pinto, I; Iosim, S; Bonet, N; Mensa-Vilaro, A; Wong, MK; Ho, G; Tormo, M; Yagüe, J; Shon, W; Wallace, DJ; Casals, F; Beck, DB; Abuav, R; Arostegui, JI October 2024
Biological & MechanisticDisease SubtypingExperimental Platforms & ModelsHuman CohortsHuman GeneticsInnate ImmunityPrecision MedicineTranslational & ClinicalAutoinflammatory DiseasesCross-Cutting & Special PopulationsRare Autoimmune DiseasesNew York University