Systemic IGF-1 gene delivery by rAAV9 improves spontaneous autoimmune peripheral polyneuropathy (SAPP)

Tong Gao,Nataliia Bogdanova,Gang Zhang,Kazim Sheikh,Sameera Ghauri,Jianxin Lin

doi:10.1038/s41598-018-23607-9

Abstract

Spontaneous autoimmune peripheral polyneuropathy (SAPP) is a mouse model of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in non-obese diabetic (NOD) mice null for costimulatory molecule, B7-2 gene (B7-2−/−). SAPP is a chronic progressive and multifocal inflammatory and demyelinating polyneuropathy of spontaneous onset with secondary axonal degeneration. Insulin-like growth factor 1(IGF-1) is a pleiotropic factor with neuroprotective, regenerative, and anti-inflammatory effects with extensive experience in its preclinical and clinical use. Systemic delivery of recombinant adeno-associated virus serotype 9 (rAAV9) provides robust and widespread gene transfer to central and peripheral nervous systems making it suitable for gene delivery in neurological diseases. A significant proportion of patients with inflammatory neuropathies like CIDP do not respond to current clinical therapies and there is a need for new treatments. In this study, we examined the efficacy IGF-1 gene therapy by systemic delivery with rAAV9 in SAPP model. The rAAV9 construct also contained a reporter gene to monitor the surrogate expression of IGF-1. We found significant improvement in neuropathic disease after systemic delivery of rAAV9/IGF-1 gene at presymptomatic and symptomatic stages of SAPP model. These findings support that IGF-1 treatment (including gene therapy) is a viable therapeutic option in immune neuropathies such as CIDP.

Highlights

Neuropathic conditions grouped under chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are the commonest acquired chronic inflammatory neuropathies encountered clinically
In Spontaneous autoimmune peripheral polyneuropathy (SAPP) model, endoneurial inflammation consists of CD4+/CD8+ T cells and monocytes/macrophages and adoptive transfer studies demonstrate that CD4+ T lymphocytes are central to the development of inflammatory neuropathy
Because of these overlapping immunopathogenic features, it is argued that SAPP is the most representative model of CIDP, and B7-2−/− mice are used in our current studies examining the efficacy of insulin-like growth factor 1 (IGF-1) gene therapy

Summary

Introduction

Neuropathic conditions grouped under chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are the commonest acquired chronic inflammatory neuropathies encountered clinically. Previous studies demonstrate that proinflammatory cytokine IFNγ plays an obligatory role in the development of neuropathy as NOD B7-2−/− and NOD.AireGW/+ mice (a dominant G228W mutation of Aire gene) deficient in IFNγ are completely protected from disease[14,15] Because of these overlapping immunopathogenic features, it is argued that SAPP is the most representative model of CIDP, and B7-2−/− mice are used in our current studies examining the efficacy of insulin-like growth factor 1 (IGF-1) gene therapy. It is reported that IGF-1 can suppress proinflammatory Th1 responses, including IFN-γ production, and promote anti-inflammatory Th2 responses[21] In this context, we examined the efficacy of IGF-1 in an animal model of CIDP due to its dual neurotrophic and immunomodulatory properties

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Conclusion