DOI: 10.1007/s13311-017-0545-8 Pages: 1-12
Article Type: Original Article

Clinical and Histopathological Amelioration of Experimental Autoimmune Encephalomyelitis by AAV Vectors Expressing a Soluble Interleukin-23 Receptor

1. Universitat Autònoma Barcelona, Institut de Neurociències (INc), Departament Bioquímica i Biologia Molecular

2. Hospital Universitari Vall d’Hebron, Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya, Vall d’Hebron Institut de Recerca

3. Universitat Autònoma de Barcelona

4. MRC National Institute for Medical Research

5. Universitat Autònoma Barcelona, IBB, Departament Biología Celular, de Fisiología y de Immunología

6. Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)

7. Institució Catalana de Recerca i Estudis Avançats (ICREA)

8. Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca

9. Universitat Autònoma Barcelona, Vector Production Unit (UPV)

Correspondence to:
Miguel Chillon
Email: miguel.chillon@uab.es

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Abstract

The role of the T helper (Th)17 pathway has been clearly demonstrated in the onset and progression of autoimmune diseases, where interleukin (IL)-23 is a key molecule in maintaining the response mediated by Th17 cells. As a consequence, recent strategies based on blocking the interaction between IL-23 and its receptor (IL-23R), for example the anti-p19 antibody tildrakizumab, have been developed to regulate the Th17 pathway from the initial stages of the disease. Here, a soluble (s)IL-23R cDNA was cloned in expression plasmids and viral vectors. The clinical efficacy of sIL-23R was evaluated in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis mice intravenously injected with a single dose of adeno-associated virus AAV8–sIL-23R vectors. Cytokine secretion was determined by multiplex assay, while histopathological analysis of the central nervous system was performed to study demyelination, inflammatory infiltration, and microglia and astroglia activation. We observed that administration of adeno-associated vector 8 encoding sIL-23R was associated with a significant disease improvement, including delay in the onset of the clinical signs; slower progress of the disease; interference with IL-23-mediated signal transducer and activator of transcription response by inhibiting of signal transducer and activator of transcription 3 phosphorylation; reduced demyelination and infiltration in the central nervous system; and lower astrocyte and microglia activation. Our results suggest that the use of vectors carrying sIL-23R to block the IL-23/IL-23R interaction may be a new therapeutic strategy for the treatment of multiple sclerosis.

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  • Online: Jun 7, 2017

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