VEXASDTVNCT07746986
DECIPHERING AND TARGETING VEXAS
An observational study of VEXAS, run by IRCCS San Raffaele at 1 site in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, men onlyHealthy volunteers can take part
- Conditions the study is for
- VEXAS
- How many people
- 60 participants
- Where
- 1 siteItaly
- Study dates
- 1 Jan 2021to 31 May 2026
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Men only
- Healthy volunteers accepted
- Adult, Older adult
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.
Who may be able to join
- 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.
Show all 9Show fewer
- 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.
Who cannot join
- Subjects not included in the previous criteria
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Devising Targeted Therapies Against VEXAS Syndrome by Untangling the Vicious Interplay of Inflammation and Clonal Dominance
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.
Read more
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.
Read the detailed description
Primary Objective. To validate, in patients affected by VEXAS syndrome, the pathogenic mechanisms associated with UBA1-mutant hematopoietic cells, with particular focus on their role in promoting systemic inflammation and clonal dominance.
Primary Endpoint. Differences in the production of pro-inflammatory cytokines/chemokines by monocytes isolated from VEXAS patients compared with healthy controls, assessed by multiplex immunoassay. The primary endpoint will be assessed on blood samples collected retrospectively.
Secondary Objectives.
- To evaluate the role of autophagy and unfolded protein response (UPR) pathways in regulating the inflammatory response in VEXAS monocytes.
- To characterize multi-omic profiles (transcriptomics, proteomics, metabolomics) of hematopoietic cells from BM and peripheral blood.
- To compare molecular profiles between UBA1-mutant cells and cells from healthy donors.
- To investigate genotype-phenotype correlations associated with different UBA1 mutations.
- To integrate ex vivo findings with data generated from in vitro models.
Secondary Endpoints.
- Changes in cytokine production following ex vivo modulation of autophagy and UPR pathways.
- Changes in transcriptomic profiles (RNA-seq) following ex vivo modulation of autophagy and UPR pathways.
- Proteomic and metabolomic profiles of hematopoietic cells from bone marrow and peripheral blood.
- Quantitative and qualitative differences across UBA1 mutation subgroups.
- Correlations between molecular data and available clinical features. Secondary endpoints will be assessed on samples collected retrospectively.
- Conditions
- VEXAS
- Keywords
- VEXAS syndrome, Inflammation, Clonal dominance, UBA1, E1 enzyme, Hematopoiesis
- Medical subject headings
- VEXAS syndrome, Inflammation
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Through study completion, an average of 1 year
Secondary outcomes (3)
Effect of autophagy and UPR modulation on inflammatory cytokine production
- Changes in cytokine production following ex vivo modulation of autophagy and UPR pathways in cells from VEXAS patients compared with healthy controls.
Measured: Through study completion, an average of 1 year
Changes in expression profiles following ex vivo modulation of autophagy and UPR pathways.
- Transcriptomic, proteomic, ubiquitomic, and metabolomic profiles of hematopoietic cells from bone marrow and peripheral blood from VEXAS patients compared with healthy controls upon ex vivo modulation of autophagy and UPR pathways.
Measured: Through study completion, an average of 1 year
Quantitative and qualitative differences across UBA1 mutation subgroups.
- Correlations between molecular data and available clinical features.
Measured: Through study completion, an average of 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Aug 2026
- Study start1 Jan 2021
- Primary completion31 May 2026
- Study completion31 May 2026
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for VEXASStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Retrospective
- Enrolment
- 60 participants (actual)
Sponsor and investigators
- Lead sponsor
- IRCCS San Raffaele
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Simone Cenci, IRCCS San Raffaele
- Investigators
- Simone Cenci, MD, Principal investigator, IRCCS Ospedale San Raffaele
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07746986
- Sponsor's protocol ID
- RF-2024-12378533 (DTV)
- Acronym
- DTV
- Status last verified
- Jul 2026
- First submitted
- 8 Jul 2026
- Last updated
- 5 Aug 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: A final decision on IPD sharing has not been made yet. The sponsor will evaluate data sharing requests on a case-by-case basis after the primary study results are published.
Publications
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.
PubMed 40195449Beck 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.
PubMed 36692560Beck 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.
PubMed 33108101
Study at a glance
From the registry record, last updated by the sponsor on 5 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Devising Targeted Therapies Against VEXAS Syndrome by Untangling the Vicious Interplay of Inflammation and Clonal Dominance
- ClinicalTrials.gov ID
- NCT07746986
- Acronym / sponsor ID
- DTV / RF-2024-12378533 (DTV)
- Conditions
- VEXAS
- Keywords
- VEXAS syndrome, Inflammation, Clonal dominance, UBA1, E1 enzyme, Hematopoiesis
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 60 participants (actual)
- Lead sponsor
- IRCCS San RaffaeleUniversity, hospital or other
- Study start
- 1 Jan 2021 (actual)
- Primary completion
- 31 May 2026 (actual)
- Study completion
- 31 May 2026 (actual)
- First posted
- 5 Aug 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Primary Objective. To validate, in patients affected by VEXAS syndrome, the pathogenic mechanisms associated with UBA1-mutant hematopoietic cells, with particular focus on their role in promoting systemic inflammation and clonal dominance.
Primary Endpoint. Differences in the production of pro-inflammatory cytokines/chemokines by monocytes isolated from VEXAS patients compared with healthy controls, assessed by multiplex immunoassay. The primary endpoint will be assessed on blood samples collected retrospectively.
Secondary Objectives.
- To evaluate the role of autophagy and unfolded protein response (UPR) pathways in regulating the inflammatory response in VEXAS monocytes.
- To characterize multi-omic profiles (transcriptomics, proteomics, metabolomics) of hematopoietic cells from BM and peripheral blood.
- To compare molecular profiles between UBA1-mutant cells and cells from healthy donors.
- To investigate genotype-phenotype correlations associated with different UBA1 mutations.
- To integrate ex vivo findings with data generated from in vitro models.
Secondary Endpoints.
- Changes in cytokine production following ex vivo modulation of autophagy and UPR pathways.
- Changes in transcriptomic profiles (RNA-seq) following ex vivo modulation of autophagy and UPR pathways.
- Proteomic and metabolomic profiles of hematopoietic cells from bone marrow and peripheral blood.
- Quantitative and qualitative differences across UBA1 mutation subgroups.
- Correlations between molecular data and available clinical features. Secondary endpoints will be assessed on samples collected retrospectively.
Study design
- Observational model
- Case-control
- Time perspective
- Retrospective
Who may qualify
- Ages
- 18 years and older
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- 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.
Key inclusion criteria (9 listed)
- Patients with VEXAS syndrome:
- Healthy donors:
Key exclusion criteria (1 listed)
- Subjects not included in the previous criteria
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Inflammatory cytokine production
Time frame: Through study completion, an average of 1 year
Differences in the production of pro-inflammatory cytokines/chemokines by monocytes isolated from VEXAS patients compared with healthy controls, assessed by multiplex immunoassay.
3 secondary outcomes
Effect of autophagy and UPR modulation on inflammatory cytokine production
Time frame: Through study completion, an average of 1 year
Changes in expression profiles following ex vivo modulation of autophagy and UPR pathways.
Time frame: Through study completion, an average of 1 year
Quantitative and qualitative differences across UBA1 mutation subgroups.
Time frame: Through study completion, an average of 1 year
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Aug 2026.
- Background: PubMed 40195449Molteni 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.
- Background: PubMed 36692560Beck 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.
- Background: PubMed 33108101Beck 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.
- Individual participant dataSharing planned: Undecided. A final decision on IPD sharing has not been made yet. The sponsor will evaluate data sharing requests on a case-by-case basis after the primary study results are published.
Related trials for VEXAS
RecruitingPhase 2
A Study to Assess the Effectiveness and Safety of Pacritinib in Patients With VEXAS Syndrome (PAXIS)
VEXAS, VEXAS Syndrome
RecruitingPhase 2
A Phase II Study of Allogeneic Hematopoietic Stem Cell Transplant for Subjects With VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic) Syndrome
Immunodeficiency, Hematopoietic Stem Cell Transplantation
Enrolling by invitationObservational study
Molecular and Clinical Analysis of Bone Marrow Failure: A Secondary Research Study
Bone Marrow Failure Disorders, VEXAS Syndrome
RecruitingPhase 2
A 52-Week Study Evaluating the Efficacy and Safety of Arumakimig (MAS825) in Participants With VEXAS Followed by Open-Label Extension (OLE) Period
VEXAS Syndrome
RecruitingPhase 2
Momelotinib in VEXAS Syndrome
VEXAS Syndome, Myelo Dysplastic Syndrome
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Simone Cenci, MD principal investigator
IRCCS Ospedale San Raffaele
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of VEXAS, run by IRCCS San Raffaele at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Inflammatory cytokine production (time frame: Through study completion, an average of 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07746986, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Aug 2026.