PMID- 28593439 OWN - NLM STAT- MEDLINE DCOM- 20180717 LR - 20240204 IS - 1878-7479 (Electronic) IS - 1933-7213 (Print) IS - 1878-7479 (Linking) VI - 14 IP - 4 DP - 2017 Oct TI - Clinical and Histopathological Amelioration of Experimental Autoimmune Encephalomyelitis by AAV Vectors Expressing a Soluble Interleukin-23 Receptor. PG - 1095-1106 LID - 10.1007/s13311-017-0545-8 [doi] AB - 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. FAU - Miralles, Marta AU - Miralles M AD - Institut de Neurociencies (INc), Departament Bioquimica i Biologia Molecular, Universitat Autonoma Barcelona, Bellaterra, Spain. FAU - Eixarch, Herena AU - Eixarch H AD - Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Multiple de Catalunya, Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Barcelona, Spain. AD - Universitat Autonoma de Barcelona, Bellaterra, Cerdanyola del Valles, 08193, Spain. FAU - Tejero, Marcos AU - Tejero M AD - Institut de Neurociencies (INc), Departament Bioquimica i Biologia Molecular, Universitat Autonoma Barcelona, Bellaterra, Spain. FAU - Costa, Carme AU - Costa C AD - Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Multiple de Catalunya, Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Barcelona, Spain. AD - Universitat Autonoma de Barcelona, Bellaterra, Cerdanyola del Valles, 08193, Spain. FAU - Hirota, Keiji AU - Hirota K AD - MRC National Institute for Medical Research, London, UK. FAU - Castano, A Raul AU - Castano AR AD - IBB, Departament Biologia Celular, de Fisiologia y de Immunologia, Universitat Autonoma Barcelona, Bellaterra, Spain. FAU - Puig, Meritxell AU - Puig M AD - Institut de Neurociencies (INc), Departament Bioquimica i Biologia Molecular, Universitat Autonoma Barcelona, Bellaterra, Spain. FAU - Stockinger, Gitta AU - Stockinger G AD - MRC National Institute for Medical Research, London, UK. FAU - Montalban, Xavier AU - Montalban X AD - Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Multiple de Catalunya, Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Barcelona, Spain. AD - Universitat Autonoma de Barcelona, Bellaterra, Cerdanyola del Valles, 08193, Spain. FAU - Bosch, Assumpcio AU - Bosch A AD - Institut de Neurociencies (INc), Departament Bioquimica i Biologia Molecular, Universitat Autonoma Barcelona, Bellaterra, Spain. AD - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain. FAU - Espejo, Carmen AU - Espejo C AD - Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Multiple de Catalunya, Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Barcelona, Spain. carmen.espejo@vhir.org. AD - Universitat Autonoma de Barcelona, Bellaterra, Cerdanyola del Valles, 08193, Spain. carmen.espejo@vhir.org. FAU - Chillon, Miguel AU - Chillon M AD - Institut de Neurociencies (INc), Departament Bioquimica i Biologia Molecular, Universitat Autonoma Barcelona, Bellaterra, Spain. miguel.chillon@uab.es. AD - Institucio Catalana de Recerca i Estudis Avancats (ICREA), Barcelona, Spain. miguel.chillon@uab.es. AD - Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Barcelona, Spain. miguel.chillon@uab.es. AD - Vector Production Unit (UPV), Universitat Autonoma Barcelona, Barcelona, Spain. miguel.chillon@uab.es. LA - eng GR - PI10-00561/Instituto de Salud Carlos III/ GR - PI15-01270/Instituto de Salud Carlos III/ GR - SGR2014-1354/Agencia de Gestio d'Ajuts Universitaris i de Recerca" (AGAUR)/ GR - SGR2014-1082/Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR)/ GR - CP07/00146; CP13/00028/Miguel Servet programme/ GR - RD07/0060/Red Espanola de Esclerosis Multiple (REEM)/ PT - Journal Article PL - United States TA - Neurotherapeutics JT - Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics JID - 101290381 RN - 0 (Receptors, Interleukin) RN - 0 (interleukin-23 receptor, mouse) SB - IM MH - Animals MH - Astrocytes/metabolism MH - Dependovirus/genetics MH - Encephalomyelitis, Autoimmune, Experimental/metabolism/*pathology/*therapy MH - Female MH - Genetic Therapy MH - Genetic Vectors/*administration & dosage/genetics MH - HEK293 Cells MH - Humans MH - Mice, Inbred C57BL MH - Microglia/metabolism MH - Multiple Sclerosis/*therapy MH - Myelitis/pathology MH - Receptors, Interleukin/genetics/*metabolism MH - Signal Transduction MH - Spinal Cord/pathology MH - Th17 Cells/metabolism PMC - PMC5722756 OTO - NOTNLM OT - AAV vector OT - EAE OT - IL-23R OT - Multiple sclerosis OT - Th17 EDAT- 2017/06/09 06:00 MHDA- 2018/07/18 06:00 PMCR- 2017/06/07 CRDT- 2017/06/09 06:00 PHST- 2017/06/09 06:00 [pubmed] PHST- 2018/07/18 06:00 [medline] PHST- 2017/06/09 06:00 [entrez] PHST- 2017/06/07 00:00 [pmc-release] AID - S1878-7479(23)01428-9 [pii] AID - 545 [pii] AID - 10.1007/s13311-017-0545-8 [doi] PST - ppublish SO - Neurotherapeutics. 2017 Oct;14(4):1095-1106. doi: 10.1007/s13311-017-0545-8.