Ex Vivo Evaluation of JAK-inhibitor and Gene Therapeutical Approach in JAK-STAT Related Disorders (JAKarta Study)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Change in STAT phosphorylation levels in peripheral blood mononuclear cells (PBMCs) after cytokine stimulation with and without JAK inhibitor exposure
研究概览
简要总结
The investigators want to study the JAK-inhibitors and their impact on the immune system and evaluate the potential of a gene-therapeutic strategy
详细描述
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:
- To study pSTAT, transcriptional profile and cytokine production on bulk and sorted peripheral blood cell populations following stimulation in the presence or absence of different jakinibs
- To evaluate to what extent jakinibs can normalize the transcriptional in different cell types (or not and identify blind spots of this treatment strategy)
- To evaluate ex vivo the impact of a gene therapeutic approach for STAT1 GOF.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Cases (A): adult patients presenting with a genetically confirmed or highly suspected disorder leading to an exagerated JAK-STAT pathway.
- •Controls (B): participants eligible for inclusion in this study must fall in one of the following categories:
- •Healthy controls (without immune-mediated disease)
排除标准
- •Children (< 18 years at time of recruitment)
- •Persons unable or unwilling to give informed consent
研究组 & 干预措施
Patients with a monogenic IEI with an hyperactive JAK-STAT pathway
Adult patients presenting with a genetically confirmed or highly suspected disorder leading to an exagerated JAK-STAT pathway.
干预措施: blood sampling (Diagnostic Test)
Healthy controls
Healthy controls (without immune-mediated disease)
干预措施: blood sampling (Diagnostic Test)
结局指标
主要结局
Change in STAT phosphorylation levels in peripheral blood mononuclear cells (PBMCs) after cytokine stimulation with and without JAK inhibitor exposure
时间窗: From time of inclusion to 24 months
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.
Change in transcriptional profiles of immune cell subsets during JAK inhibitor treatment
时间窗: From time of inclusion to 24 months
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)
Impact of ex vivo gene therapeutic correction in STAT1 gain-of-function patient-derived PBMCs
时间窗: 24 months from inclusion
On-target editing efficiency measured as percentage of corrected alleles by targeted sequencing.
次要结局
- Mutation-specific differences in response to JAK inhibitor treatment(From time of inclusion to 24 months)
- Impact of our gene therapeutic approach on cell viability(From time of inclusion to 24 months)
- Off target events in our ex vivo gene therapeutic approach(24 months)
- Transcriptional correction of our ex vivo gene therapeutic approach(24 months)
- Functional differentiation capacity of gene therapy-corrected cells(24 months)
研究者
prof. dr. Rik Schrijvers
Prof. dr.
Universitaire Ziekenhuizen KU Leuven