title: Gene therapy with mesenchymal stem cells expressing IFN-ß ameliorates neuroinflammation in experimental models of multiple sclerosis.
abstract: Recombinant IFN-ß is one of the first-line treatments in multiple sclerosis (MS), despite its lack of efficacy in some patients. In this context, mesenchymal stem cells (MSCs) represent a promising therapeutic alternative due to their immunomodulatory properties and multipotency. Moreover, by taking advantage of their pathotropism, these cells can be genetically modified to be used as carriers for delivering or secreting therapeutic drugs into injured tissues. Here, we report the therapeutic effect of systemic delivery of adipose-derived MSCs (AdMSCs), transduced with the IFN-β gene, into mice with experimental autoimmune encephalomyelitis (EAE).
  
  
  
  Relapsing-remitting and chronic progressive EAE were induced in mice. Cells were injected i.v. Disease severity, inflammation and tissue damage were assessed clinically, by flow cytometry of spleens and histopathological evaluation of the CNS respectively.
  
  
  
  Genetic engineering did not modify the biological characteristics of these AdMSCs (morphology, growth rate, immunophenotype and multipotency). Furthermore, the transduction of IFN-ß to AdMSCs maintained and, in some cases, enhanced the functional properties of AdMSCs by ameliorating the symptoms of MS in EAE models and by decreasing indications of peripheral and central neuro-inflammation.
  
  
  
  Gene therapy was found to be more effective than cell therapy in ameliorating several clinical parameters in both EAE models, presumably due to the continuous expression of IFN-β. Furthermore, it has significant advantages over AdMSC therapy, and also over systemic IFN-ß treatment, by providing long-term expression of the cytokine at therapeutic concentrations and reducing the frequency of injections, while minimizing dose-limiting side effects.
authors.affiliation: Unidad de Gestión Clínica Inter-centros de Neurociencias, Laboratorio de Investigación y Servicio de Neurología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Marin-Bañasco
authors.affiliation: Cell and Gene Therapy Group, Genomic Medicine Department, GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Granada, Spain.
authors.forename: K
authors.initials: K
authors.lastname: Benabdellah
authors.affiliation: Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC, 28002, Madrid, Spain.|Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, 45071, Toledo, Spain.|Red Española de Esclerosis Múltiple (REEM), Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Melero-Jerez
authors.affiliation: Unidad de Gestión Clínica Inter-centros de Neurociencias, Laboratorio de Investigación y Servicio de Neurología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Spain.|Red Española de Esclerosis Múltiple (REEM), Barcelona, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Oliver
authors.affiliation: Unidad de Gestión Clínica Inter-centros de Neurociencias, Laboratorio de Investigación y Servicio de Neurología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Spain.|Red Española de Esclerosis Múltiple (REEM), Barcelona, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Pinto-Medel
authors.affiliation: Unidad de Gestión Clínica Inter-centros de Neurociencias, Laboratorio de Investigación y Servicio de Neurología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Hurtado-Guerrero
authors.affiliation: Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC, 28002, Madrid, Spain.|Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos, 45071, Toledo, Spain.|Red Española de Esclerosis Múltiple (REEM), Barcelona, Spain.
authors.forename: F
authors.initials: F
authors.lastname: de Castro
authors.affiliation: Grupo de Neuroinmuno-Reparación, Hospital Nacional de Parapléjicos, 45071, Toledo, Spain.|Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos, 45071, Toledo, Spain.|Red Española de Esclerosis Múltiple (REEM), Barcelona, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Clemente
authors.affiliation: Unidad de Gestión Clínica Inter-centros de Neurociencias, Laboratorio de Investigación y Servicio de Neurología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Spain.|Red Española de Esclerosis Múltiple (REEM), Barcelona, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Fernández
authors.affiliation: Cell and Gene Therapy Group, Genomic Medicine Department, GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Granada, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Martin
authors.affiliation: Unidad de Gestión Clínica Inter-centros de Neurociencias, Laboratorio de Investigación y Servicio de Neurología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Spain.|Red Española de Esclerosis Múltiple (REEM), Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Leyva
authors.affiliation: Unidad de Gestión Clínica Inter-centros de Neurociencias, Laboratorio de Investigación y Servicio de Neurología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Spain.|Red Española de Esclerosis Múltiple (REEM), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Suardíaz
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D016899:Interferon-beta / Q000235:genetics*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D020528:Multiple Sclerosis, Chronic Progressive / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D012720:Severity of Illness Index
chemical_list: D016899:Interferon-beta