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| ID | Type | Description | Link |
|---|---|---|---|
| G054022N | Other Grant/Funding Number | Fonds Wetenschapelijk Onderzoek Flanders (FWO) |
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| Name | Class |
|---|---|
| Research Foundation - Flanders (Fonds Wetenschappelijk Onderzoek) | OTHER |
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The investigators want to study the JAK-inhibitors and their impact on the immune system and evaluate the potential of a gene-therapeutic strategy
The investigators want to study ex vivo the effect of JAK-inhibitors on the transcriptional profile and immune cell landscape in patients with inborn errors of the JAK-STAT pathway and the ex vivo evaluation of the feasibility of a gene therapeutic approach for STAT1 GOF. Following aspects will be compared:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Patients with a monogenic IEI with an hyperactive JAK-STAT pathway | Other | Adult patients presenting with a genetically confirmed or highly suspected disorder leading to an exagerated JAK-STAT pathway. |
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| Healthy controls | Other | Healthy controls (without immune-mediated disease) |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| blood sampling | Diagnostic Test | Blood/serum samples will be collected during routine clinical visits at the time of planned peripheral venous blood sampling. Samples will be processed and either used immediately (flow cytometry-based cell sorting, gDNA extraction, in vitro functional assays, primary cell culture or single-cell applications) or stored for later analysis. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in STAT phosphorylation levels in peripheral blood mononuclear cells (PBMCs) after cytokine stimulation with and without JAK inhibitor exposure | Quantification via Median fluorescence intensity (MFI) of phosphorylated STAT1, STAT3, and STAT5 using multiparameter flow cytometry in bulk PBMCs and sorted T cells, B cells, NK cells, and monocyte subsets after standardized cytokine stimulation (e.g., IFNα, IFNγ, IL-6, IL-2) with or without JAK inhibitor exposure. Outcomes reported as fold-change relative to baseline. | From time of inclusion to 24 months |
| Change in transcriptional profiles of immune cell subsets during JAK inhibitor treatment | Differential gene expression assessed by single-cell RNA sequencing of PBMCs. Outcome is reported as the number of differentially expressed genes (adjusted p<0.05) at different sampling timepoints (n=3) | From time of inclusion to 24 months |
| Impact of ex vivo gene therapeutic correction in STAT1 gain-of-function patient-derived PBMCs | On-target editing efficiency measured as percentage of corrected alleles by targeted sequencing. | 24 months from inclusion |
| Measure | Description | Time Frame |
|---|---|---|
| Mutation-specific differences in response to JAK inhibitor treatment | Comparison of cytokine-induced phosphorylation (MFI of pSTAT1, pSTAT3, pSTAT5) and transcriptional responses (differential expression and pathway enrichment) between patients harboring distinct STAT1 gain-of-function variants. Outcomes reported as half-inhibitory concentration IC50 and area under the curve AUC in comparison to baseline |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Rik Schrijvers, MD, PhD | Contact | +3216342985 | rik.schrijvers@uzleuven.be |
| Name | Affiliation | Role |
|---|---|---|
| Rik Schrijvers, MD, PhD | UZ Leuven | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospitals Leuven, | Recruiting | Leuven | Vlaams-Brabant | 3000 | Belgium |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37020552 | Background | Staels F, Roosens W, Giovannozzi S, Moens L, Bogaert J, Iglesias-Herrero C, Gijsbers R, Bossuyt X, Frans G, Liston A, Humblet-Baron S, Meyts I, Van Aelst L, Schrijvers R. Case report: Myocarditis in congenital STAT1 gain-of function. Front Immunol. 2023 Mar 20;14:1095595. doi: 10.3389/fimmu.2023.1095595. eCollection 2023. | |
| 33679782 |
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| ID | Term |
|---|---|
| D000081207 | Primary Immunodeficiency Diseases |
| ID | Term |
|---|---|
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D001800 | Blood Specimen Collection |
| ID | Term |
|---|---|
| D013048 | Specimen Handling |
| D019411 | Clinical Laboratory Techniques |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
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This is a parallel assignment study with two arms: (1) patients diagnosed with [rare disease] who will receive [describe treatment] and have blood drawn at specific time points, and (2) healthy controls who will undergo matched blood sampling for comparative analysis. Healthy controls will not receive the intervention.
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| From time of inclusion to 24 months |
| Impact of our gene therapeutic approach on cell viability | Cell viability will be measured with MTT-assay | From time of inclusion to 24 months |
| Off target events in our ex vivo gene therapeutic approach | Off-target events detected by GUIDE-seq and confirmed by amplicon sequencing. | 24 months |
| Transcriptional correction of our ex vivo gene therapeutic approach | Transcriptional correction measured by single-cell RNA sequencing (fold-change of interferon pathway gene expression). | 24 months |
| Functional differentiation capacity of gene therapy-corrected cells | Functional differentiation capacity of corrected cells assessed by flow cytometry (percentages of T, B, NK, and monocyte subsets). | 24 months |
| Giovannozzi S, Demeulemeester J, Schrijvers R, Gijsbers R. Transcriptional Profiling of STAT1 Gain-of-Function Reveals Common and Mutation-Specific Fingerprints. Front Immunol. 2021 Feb 17;12:632997. doi: 10.3389/fimmu.2021.632997. eCollection 2021. |
| 32582194 | Background | Giovannozzi S, Lemmens V, Hendrix J, Gijsbers R, Schrijvers R. Live Cell Imaging Demonstrates Multiple Routes Toward a STAT1 Gain-of-Function Phenotype. Front Immunol. 2020 Jun 9;11:1114. doi: 10.3389/fimmu.2020.01114. eCollection 2020. |
| D011677 | Punctures |
| D013514 | Surgical Procedures, Operative |
| D008919 | Investigative Techniques |