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Ex Vivo Evaluation of JAK-inhibitor and Gene Therapeutical Approach in JAK-STAT Related Disorders

ConditionPrimary Immunodeficiency Diseases (PID)
Trial statusRecruiting
Trial phaseNot applicable
Trial typeInterventional
Biological sexAll
Age18+
Sponsorprof. dr. Rik Schrijvers

About this trial

The investigators want to study the JAK-inhibitors and their impact on the immune system and evaluate the potential of a gene-therapeutic strategy

Eligibility criteria

This trial accepts healthy volunteers

Qualifiers

Cases (A): adult patients presenting with a genetically confirmed or highly suspected disorder leading to an exagerated JAK-STAT pathway.

Healthy controls (without immune-mediated disease)

Disqualifiers

Children (< 18 years at time of recruitment)

Persons unable or unwilling to give informed consent

Trial design

Design model

Parallel

Treatments tested in this trial

  • 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.

Treatment groups

20 Participants
are divided into 2 treatment groups
Group A: Patients with a monogenic IEI with an hyperactive JAK-STAT pathwayOther 1 intervention
Group B: Healthy controlsOther 1 intervention

Trial outcomes

Primary outcomes

1

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.

Time frame
From time of inclusion to 24 months
2

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)

Time frame
From time of inclusion to 24 months
3

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.

Time frame
24 months from inclusion

Secondary outcomes

1

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

Time frame
From time of inclusion to 24 months
2

Impact of our gene therapeutic approach on cell viability

Cell viability will be measured with MTT-assay

Time frame
From time of inclusion to 24 months
3

Off target events in our ex vivo gene therapeutic approach

Off-target events detected by GUIDE-seq and confirmed by amplicon sequencing.

Time frame
24 months
4

Transcriptional correction of our ex vivo gene therapeutic approach

Transcriptional correction measured by single-cell RNA sequencing (fold-change of interferon pathway gene expression).

Time frame
24 months

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

prof. dr. Rik Schrijvers

Lead sponsor

Universitaire Ziekenhuizen KU Leuven

Sponsor institution

Research Foundation - Flanders (Fonds Wetenschappelijk Onderzoek)

Collaborator

Source ClinicalTrials.gov
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