Fibronectin peptide antagonism for chronic inflammatory neuropathies

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DESCRIPTION: Our objective is to evaluate whether inhibition of fibronectin-dependent leukocyte infiltration into peripheral nerves is a specific therapy for chronic peripheral nerve inflammation seen in immune-mediated disorders and neuropathic pain. 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 peripheral neuritis? 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 recruitment of pathogenic hematogenous mononuclear leukocytes 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 and neuropathic pain. 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 progressive chronic peripheral nerve inflammation, demyelination and axonal injury in a severe, reliable CIDP mouse model, using our published methods. Current therapies for CIDP and other peripheral nerve inflammatory disorders, including neuropathic pain 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, as well as neuropathic pain.