DECIPHERING AND TARGETING VEXAS

NCT07746986 | Completed

• 1 other identifier: RF-2024-12378533 (DTV)
• Study Type: observational
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome (1/4,000 males aged \>50) is a paradigmatic age-onset acquired, severe, autoinflammatory hematological disease due to clonal dominance of hematopoietic cells bearing a somatic mutation in the UBA1 (ubiquitin-activating enzyme 1) gene. VEXAS presents with treatment-refractory systemic myeloid-driven inflammatory manifestations and hematologic abnormalities, hence the poor prognosis. Current available therapies are poorly effective and burdened by debilitating side effects. VEXAS mutations inactivate cytoplasmic UBA1-driven ubiquitination, impairing protein clearance and triggering stress responses. By innovative base-editing (patent PCTIB2024060412), the investigators generated new in vitro and in vivo models that, along with comprehensive phenotyping of VEXAS patients, disclosed progressive inflammatory poisoning of healthy hematopoiesis and resilience to inflammation of UBA1-mutant hematopoietic stem/progenitor cells (HSPC) as key mechanisms of inflammation and clonal dominance. Deciphering these mechanisms might reveal predictive markers, actionable targets, and inform drug repurposing or novel therapies. The investigators hypothesize that cell-intrinsic and -extrinsic mechanisms triggered by altered UBA1 function are targetable drivers linking inflammation and clonal dominance. The research plan is designed to investigate, both in vitro and in BM and peripheral hematopoietic cells from VEXAS patients, the key pathogenic mechanisms sustaining inflammation and clonal dominance in VEXAS syndrome. Patients with VEXAS syndrome, defined by the presence of pathogenic mutations in the UBA1 gene identified in hematopoietic cells isolated from the peripheral blood of individuals with systemic autoinflammatory disease, will be included in the study population. The study will also enroll healthy control subjects, matched as closely as possible for age and sex, with no history of inflammatory or hematologic disorders. The dissection of mechanisms underlying the interplay between inflammation and clonal dominance will be fundamental to identify novel therapeutic strategies against disease progression that would enable the treatment of VEXAS patients at early disease stages, improving prognosis and life expectancy. Moreover, establishing robust genotype-to-phenotype correlations in patients may inform the design of personalized therapeutic options. The obtained results may inform the design of new therapeutic strategies against this cureless disease. Overall, in this observational monocentric study the investigators will use retrospective samples collected from 2020 to 2026 to conduct cytokine profiling and comprehensive omics-based characterization (transcriptomics, proteomics, metabolomics) on peripheral blood-derived monocytes/neutrophils and bone marrow (BM) hematopoietic cells.

Conditions

VEXAS

Keywords

VEXAS syndrome; Inflammation; Clonal dominance; UBA1; E1 enzyme; Hematopoiesis

Outcome Measures

Primary Outcomes (1)

• Inflammatory cytokine production

  Differences in the production of pro-inflammatory cytokines/chemokines by monocytes isolated from VEXAS patients compared with healthy controls, assessed by multiplex immunoassay.

  Through study completion, an average of 1 year

Secondary Outcomes (3)

• Effect of autophagy and UPR modulation on inflammatory cytokine production

  Through study completion, an average of 1 year

• Changes in expression profiles following ex vivo modulation of autophagy and UPR pathways.

  Through study completion, an average of 1 year

• Quantitative and qualitative differences across UBA1 mutation subgroups.

  Through study completion, an average of 1 year

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Male gender
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients aged 18 and older diagnosed with VEXAS syndrome by identification of pathogenic mutations in the UBA1 gene in hematopoietic cells isolated from peripheral blood in the presence of systemic autoinflammatory disease.

You may qualify if:

• Patients with VEXAS syndrome:
• Diagnosed with VEXAS syndrome by identification of pathogenic mutations in the UBA1 gene in hematopoietic cells isolated from peripheral blood in the presence of systemic autoinflammatory disease.
• Age \>18.
• BM and peripheral blood samples were collected between 2020 and 2026.
• Healthy donors:
• In good general health as evidenced by medical history, with no history of inflammatory or hematologic disorders. BM samples derive from subjetcs undergoing hip replacement.
• Matched as closely as possible with VEXAS patients by age and sex.
• Age \>18.
• BM and peripheral blood samples were collected between 2020 and 2026.

You may not qualify if:

• Subjects not included in the previous criteria

Sponsors & Collaborators

• IRCCS San Raffaele: lead

Study Sites (1)

IRCCS Ospedale San Raffaele

Milan, MI, 20129, Italy

Location

Related Publications (3)

• Molteni R, Fiumara M, Campochiaro C, Alfieri R, Pacini G, Licari E, Tomelleri A, Diral E, Varesi A, Weber A, Quaranta P, Albano L, Gaddoni C, Basso-Ricci L, Stefanoni D, Alessandrini L, Degl'Innocenti S, Sanvito F, Bergonzi GM, Annoni A, Panigada M, Cantoni E, Canarutto D, Xie SZ, D'Alessandro A, Di Micco R, Aiuti A, Ciceri F, De Luca G, Dagna L, Matucci-Cerinic M, Merelli I, Cenci S, Scala S, Cavalli G, Naldini L, Ferrari S. Mechanisms of hematopoietic clonal dominance in VEXAS syndrome. Nat Med. 2025 Jun;31(6):1911-1924. doi: 10.1038/s41591-025-03623-9. Epub 2025 Apr 7.

  PMID: 40195449 BACKGROUND

• Beck DB, Bodian DL, Shah V, Mirshahi UL, Kim J, Ding Y, Magaziner SJ, Strande NT, Cantor A, Haley JS, Cook A, Hill W, Schwartz AL, Grayson PC, Ferrada MA, Kastner DL, Carey DJ, Stewart DR. Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population. JAMA. 2023 Jan 24;329(4):318-324. doi: 10.1001/jama.2022.24836.

  PMID: 36692560 BACKGROUND

• Beck DB, Ferrada MA, Sikora KA, Ombrello AK, Collins JC, Pei W, Balanda N, Ross DL, Ospina Cardona D, Wu Z, Patel B, Manthiram K, Groarke EM, Gutierrez-Rodrigues F, Hoffmann P, Rosenzweig S, Nakabo S, Dillon LW, Hourigan CS, Tsai WL, Gupta S, Carmona-Rivera C, Asmar AJ, Xu L, Oda H, Goodspeed W, Barron KS, Nehrebecky M, Jones A, Laird RS, Deuitch N, Rowczenio D, Rominger E, Wells KV, Lee CR, Wang W, Trick M, Mullikin J, Wigerblad G, Brooks S, Dell'Orso S, Deng Z, Chae JJ, Dulau-Florea A, Malicdan MCV, Novacic D, Colbert RA, Kaplan MJ, Gadina M, Savic S, Lachmann HJ, Abu-Asab M, Solomon BD, Retterer K, Gahl WA, Burgess SM, Aksentijevich I, Young NS, Calvo KR, Werner A, Kastner DL, Grayson PC. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med. 2020 Dec 31;383(27):2628-2638. doi: 10.1056/NEJMoa2026834. Epub 2020 Oct 27.

  PMID: 33108101 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Biological samples will include peripheral blood samples and bone marrow blood samples obtained from bone marrow aspirates or bone biopsies (orthopaedic procedures).

MeSH Terms

Conditions

VEXAS syndrome; Inflammation

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Simone Cenci, MD

  IRCCS Ospedale San Raffaele

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: July 8, 2026
• First Posted: August 5, 2026
• Study Start: January 1, 2021
• Primary Completion: May 31, 2026
• Study Completion: May 31, 2026
• Last Updated: August 5, 2026

Record last verified: 2026-07

Locations

IT (1)