Recombinant adenosine deaminase ameliorates inflammation, vascular disease and fibrosis in murine models of systemic sclerosis

重组腺苷脱氨酶可改善系统性硬化症小鼠模型的炎症、血管疾病和纤维化

• 批准号: 417886775
• 负责人: Dr. Yun Zhang
• 金额: --
• 依托单位: Klinik für Rheumatologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/417886775?language=en
• 关键词: Recombinant; adenosine; deaminase; ameliorates; inflammation

Fibrotic diseases are characterized by excessive deposition of extracellular matrix with perturbation of the physiological tissue architecture and impairment of the physiological function of the affected organs. Fibrotic tissue remodeling imposes a major burden on modern societies and has been estimated to contribute to up to 45% of deaths in the developed world. In addition to fibrosis, Systemic sclerosis (SSc) patients are also suffering from inflammatory manifestations and vascular alterations affecting either the pulmonary arteries resulting in pulmonary arterial hypertension (PAH) or smaller vessels at the extremities manifesting as Raynaud´s syndrome and ischemic ulcers, which contribute to the high morbidity and mortality of SSc patients. Thus, there is a huge medical need for effective disease modifying therapies that simultaneously target the vascular alterations, inflammation and tissue fibrosis in SSc.In the preliminary results, we demonstrate that treatment with PEGylated adenosine deaminase (pegADA) inhibited proliferation of pulmonary vascular smooth muscle cells and apoptosis of microvascular endothelial cells in Fra2-transgenic mice, thereby ameliorating PAH and microangiopathic features in this preclinical model. pegADA also effectively blocked myofibroblast differentiation and reduced pulmonary, dermal and myocardial fibrosis in Fra2-transgenic mice and in experimental sclerodermatous chronic graft-versus-host diseases (cGvHD). Treatment with pegADA decreased inflammation with reduced ILC2 numbers, impaired M2 / Th2-polarization and reduced production of profibrotic cytokines. In the proposed project, we will use a comprehensive collection of state-of-the-art in vitro and in in vivo preclinical models, to profile the intracellular pathways that are modulated by adenosine in target cells, to compare the efficacy of pegADA with individual or combined inhibition of adenosine receptors or CD73 and to investigate the efficacy of treatment with pegADA in preclinical models of other fibrotic diseases.

纤维化疾病的特征在于细胞外基质的过度沉积，伴随着生理组织结构的扰动和受影响器官的生理功能的损害。纤维化组织重塑给现代社会带来了重大负担，据估计，在发达国家，纤维化组织重塑导致高达45%的死亡。除了纤维化，系统性硬化症（SSc）患者还患有炎症表现和血管改变，影响肺动脉，导致肺动脉高压（PAH）或四肢小血管，表现为雷诺综合征和缺血性溃疡，这导致SSc患者的高发病率和死亡率。因此，有一个巨大的医疗需求，有效的疾病修饰疗法，同时靶向血管的变化，炎症和组织纤维化在SSc.In初步结果，我们证明，治疗与聚乙二醇化腺苷脱氨酶（pegADA）抑制肺血管平滑肌细胞的增殖和微血管内皮细胞的凋亡在Fra 2转基因小鼠，从而改善该临床前模型中的PAH和微血管病变特征。在Fra 2转基因小鼠和实验性硬皮病慢性移植物抗宿主病（cGvHD）中，pegADA还有效地阻断肌成纤维细胞分化并减少肺、皮肤和心肌纤维化。用pegADA治疗减少炎症，减少ILC 2数量，损害M2 /Th 2极化和减少促纤维化细胞因子的产生。在拟议的项目中，我们将使用最先进的体外和体内临床前模型的全面收集，以分析靶细胞中腺苷调节的细胞内途径，比较pegADA与腺苷受体或CD 73的单独或联合抑制的疗效，并研究pegADA治疗其他纤维化疾病的临床前模型的疗效。