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

纤维化疾病的特点是细胞外基质过度沉积，生理组织结构受到干扰，受累器官的生理功能受损。纤维化组织重塑给现代社会造成了重大负担，据估计，发达国家高达45%的死亡是由纤维化组织重塑造成的。除了纤维化外，系统性硬化症（SSc）患者还会出现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，这些都是导致SSc患者高发病率和死亡率的原因。因此，对于同时针对SSc的血管改变、炎症和组织纤维化的有效疾病修饰疗法存在巨大的医学需求。在初步结果中，我们证明了聚乙二醇化腺苷脱氨酶（pegADA）抑制了fra2转基因小鼠肺血管平滑肌细胞的增殖和微血管内皮细胞的凋亡，从而改善了临床前模型中的PAH和微血管病变特征。在fra2转基因小鼠和实验性硬皮病慢性移植物抗宿主病（cGvHD）中，pegADA还能有效阻断肌成纤维细胞分化，减少肺、皮肤和心肌纤维化。pegADA治疗通过降低ILC2数量、损害M2 / th2极化和减少促纤维化细胞因子的产生来减轻炎症。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综合收集，来分析靶细胞中由腺苷调节的细胞内通路，比较pegADA与单独或联合抑制腺苷受体或CD73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。

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.