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
- 2
- 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
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