Understanding shared mechanisms of response to targeted therapies for eczema

了解湿疹靶向治疗的共同反应机制

• 批准号: 2888969
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2888969
• 关键词: Understanding; shared; mechanisms; response; targeted

Atopic eczema is a common inflammatory skin disease, affecting 20% of children and 10% of adults1,2. It is characterised by epidermal barrier dysfunction and excessive production of Th2 inflammatory mediators (IL-4/IL-13).Recent research has delivered therapies targeting these immune molecules, with dupilumab (a monoclonal antibody biologic blocking IL-4 and IL-13) and Janus kinase (JAK) inhibitors (downregulating multiple cytokines, including IL-4 and IL-13) showing major benefit3. However, these high-cost drugs (~£10,000 per patient per year) add to the already substantial economic burden of disease. A recent network meta-analysis further highlighted inter-individual heterogeneity in drug response and tolerability4. Patients often cycle through multiple drugs to achieve disease control, experiencing flares, infection, adverse effects. More than 60% fail to achieve clear/nearly clear skin on dupilumab and JAK inhibitors7-10. Eye side-effects impact more than 50% of those on dupilumab and herpes zoster is the commonest infectious complication of JAK inhibitors11-13.These problems reflect the limited understanding of how these drugs work5,6. Prior studies using the limited resolution of microarray and bulk RNA-seq suggest the action of different therapies ultimately converge on shared suppression of the central pathogenic Th2 axis by 12-16 weeks of treatment7,8. There is, however, a lack of head-to head comparator data and a paucity of mechanistic research into early treatment effects. This has led to a poor understanding of primary drug consequences as opposed to secondary/downstream effects of inhibiting inflammatory cascades. The NIHR-funded BEACON multi-arm trial is a globally unique opportunity to address this important research gap.Commencing Q2 2023 (co-lead Smith), it will provide the first head-to-head evidence on comparative clinical effectiveness, tolerability and cost effectiveness of the major classes of eczema therapies. In this context, single cell (including single nuclear) methods have the potential to provide high resolution mechanistic insights into treatmentactions 9-11. The power of this technology is exemplified in cancer research, where it has illuminated the evolution of tumour immune infiltrates during immunotherapy9,12. Conversely, in eczema there is a paucity of single cell data on treatment effects and no comparative analyses of novel targeted therapies13. Question: What are the critical early events that mediate shared response to targeted therapies in eczema?Hypothesis: Different targeted therapies share early mechanisms of action that are critical to their ultimate effects on Th2 suppression in eczema.Objective: To intersect the early actions of the targeted therapies dupilumab (biologic) and JAK inhibitors in BEACONparticipants who show a clinical response to these drugs. This will uncover early shared changes that drive eczema resolution.Aim 1: Identify early changes in skin cell subpopulations, cell-cell interactions and gene regulatory networks that underpin treatment actions and converge upon Th2 axis suppression using single nuclear RNA-seq (snRNA-seq).Aim 2: Define the spatial context of the cell subpopulations and cell-cell interactions underpinning treatment actionsin skin (as identified in Aim 1). Aim 3: Characterise the cell subpopulations implicated in drug action and response in blood by immune profiling matched blood samples from the BEACON cohort.

特应性湿疹是一种常见的炎症性皮肤病，影响20％的儿童和10％的成人1,2。它的特征是表皮屏障功能障碍和Th2炎症介质的过量产生（IL-4/IL-13）。进行的研究提供了针对这些免疫分子的治疗方法，并用dupilumab（dupilumab）（包括单克隆抗体生物学的生物学阻断IL-4和IL-13）和Janus kinus kinus kinnegine（Janus Kinnegine insirientians）（Janus kinus kinus kinus insrigitians in nig in ins insrigations）（Janus Kinnecrient）（Janus Kinnecriens）indrigiations（Janus kinus kinus insrigition），对IL-4和IL-13）显示了主要好处3。但是，这些高成本药物（每年约10,000英镑）增加了已经大量的疾病经济燃烧。最近的网络荟萃分析进一步强调了药物反应和耐受性的个体间异质性4。患者经常通过多种药物循环以获得疾病控制，体验耀斑，感染和不良反应。超过60％的人无法在Dupilumab和Jak抑制剂7-10上获得清晰/几乎清晰的皮肤。眼睛副作用影响杜皮鲁姆单抗和带状疱疹的50％以上是JAK抑制剂11-13的最常见感染并发症。这些问题反映了对这些药物如何起作用的有限理解5,6。先前使用微阵列和大量RNA-seq分辨率有限分辨率的研究表明，不同疗法的作用最终会在治疗12-16周的治疗中汇聚在共同抑制中央致病性TH2轴上的共同抑制作用7,8。但是，缺乏头对头比较器数据以及对早期治疗效果的机械研究很少。与抑制炎症性级联反应的继发性/下游作用相比，这导致对主要药物后果的理解不足。 NIHR资助的Beacon Multi-Arm试验是解决这一重要的研究差距的全球独特机会。教会Q2 2023（共同领导）Smith）将为浮肿疗法的主要类别提供比较临床有效性，耐受性和成本效益的首个面对面的证据。在这种情况下，单细胞（包括单个核）方法具有对治疗动作的高分辨率机理见解9-11的潜力。该技术在癌症研究中免除了该技术的能力，在癌症研究中，它在免疫疗法期间阐明了肿瘤免疫疗法的演变9,12。相反，在湿疹中，关于治疗效果的单细胞数据很少，没有对新型靶向疗法的比较分析13。问题：中位数对湿疹中靶向疗法的共同反应的关键早期事件是什么？假设：不同的靶向疗法具有早期的作用机制，这对于它们对ezema中Th2抑制的最终作用至关重要。目标：与靶向疗法dupilumab（生物学）和JAK抑制剂的靶向疗法的早期作用相结合，以表明该临床司法机构的临床抑制剂。这将揭示早期共享的变化，以驱动湿疹分辨率。IAM1：确定皮肤细胞亚群，细胞 - 细胞相互作用和基因调节网络的早期变化，这些变化是基础治疗动作并在Th2轴上抑制抑制th2轴的早期变化。使用单个核RNA-SEQ（SNRNA-SEQ）.AIM 2：定义细胞亚群相互作用的空间上下文，以识别细胞量和细胞量下的brice skinning（AL AR AIM PINSPINS）。 AIM 3：表征通过免疫分析与信标队列相匹配的血液样本在药物作用和血液反应中实施的细胞亚群。