Fibronectin peptide antagonism for chronic inflammatory neuropathies

描述（由申请人提供）：我们的目的是评价抑制纤连蛋白依赖性白细胞浸润到周围神经中是否是慢性周围神经炎症的特异性疗法。使用慢性炎症性脱髓鞘性多发性神经根神经病（CIDP）作为持续性周围神经炎症的一个例子，导致显着的长期残疾，我们建议解决一个基本问题：竞争性拮抗纤维连接蛋白连接段1（FN CS1）CIDP的一个潜在的治疗策略？基于我们使用体外和体内方法的令人兴奋的新的初步数据，我们提出了以下假设：内皮FN CS1积极参与CIDP中病原性单核白细胞从血流中穿过血神经屏障的运输。作为这一点的延伸，我们提出，竞争性抑制与FN CS1肽拮抗剂将减少白细胞运输的血神经屏障。白细胞浸润的减少将限制长期外周神经炎症、脱髓鞘和轴突损伤的有害后果。这一策略为开发CIDP的新型靶向治疗提供了机会。为了解决这一假设，我们将确定竞争性FN CS1肽阻断减少未经治疗的CIDP患者外周血单核白细胞在一种新的尼古丁刺激的人体外血神经屏障模型，包括毛细血管流速的运输。贩运活动将通过视频显微镜实时捕捉和量化。我们还将评估这种肽拮抗剂的影响，持续的慢性外周神经炎症，脱髓鞘和轴突损伤的严重CIDP小鼠模型的行为，电生理和组织病理学特征，使用我们公布的方法。目前CIDP和其他周围神经炎性疾病的治疗是非特异性的，部分有效。该提案是FN CS1肽拮抗作用作为CIDP靶向抗炎治疗的临床前评价。抑制疾病特异性炎症通路有可能彻底改变慢性外周神经炎症的治疗。拟议的工作可能会导致开发新的小分子拮抗剂，用于CIDP和其他慢性炎症性神经病变的I期临床试验。

DESCRIPTION (provided by applicant): Our objective is to evaluate whether inhibition of fibronectin-dependent leukocyte infiltration into peripheral nerves is a specific therapy for chronic peripheral nerve inflammation. Using chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as an example of persistent peripheral nerve inflammation that results in significant long-term disability, we propose to address a fundamental question: Is competitive antagonism of fibronectin connecting segment-1 (FN CS1) a potential treatment strategy for CIDP? Based on our exciting new preliminary data using in vitro and in vivo approaches, we propose the following hypothesis: Endothelial FN CS1 actively participates in the trafficking of pathogenic mononuclear leukocytes from the bloodstream across the blood-nerve barrier in CIDP. As an extension of this, we propose that competitive inhibition with a FN CS1 peptide antagonist would reduce leukocyte trafficking at the blood-nerve barrier. Reduction in leukocyte infiltration would limit the harmful consequences of prolonged peripheral nerve inflammation, demyelination and axonal injury. This strategy provides an opportunity to develop a novel targeted therapy for CIDP. In order to address this hypothesis, we will determine that competitive FN CS1 peptide blockade reduces trafficking of untreated CIDP patient peripheral blood mononuclear leukocytes on a novel cytokine-stimulated human in vitro blood-nerve barrier model that incorporates capillary flow rates. Trafficking events would be captured real-time and quantified by video microscopy. We will also evaluate the effect of this peptide antagonist on the behavioral, electrophysiological and histopathological features of persistent chronic peripheral nerve inflammation, demyelination and axonal injury in a severe mouse model of CIDP, using our published methods. Current therapies for CIDP and other peripheral nerve inflammatory disorders are non-specific and partly effective. This proposal is a preclinical evaluation of FN CS1 peptide antagonism as a targeted anti-inflammatory therapy for CIDP. Inhibiting disease-specific inflammatory pathways has the potential to revolutionize the treatment of chronic peripheral nerve inflammation. The proposed work could lead towards the development of novel, small molecular antagonists for phase I clinical trials in CIDP and other chronic inflammatory neuropathies.