title: Gene therapy of multiple sclerosis using interferon β-secreting human bone marrow mesenchymal stem cells.
abstract: Interferon-beta (IFN- β ), a well-established standard treatment for multiple sclerosis (MS), has proved to exhibit clinical efficacy. In this study, we first evaluated the therapeutic effects for MS using human bone marrow-derived mesenchymal stem cells (hBM-MSCs) as delivery vehicles with lesion-targeting capability and IFN- β as therapeutic gene. We also engineered hBM-MSCs to secret IFN- β (MSCs-IFN β ) via adenoviral transduction and confirmed the secretory capacity of MSCs-IFN β by an ELISA assay. MSCs-IFN β -treated mice showed inhibition of experimental autoimmune encephalomyelitis (EAE) onset, and the maximum and average score for all animals in each group was significantly lower in the MSCs-IFN β -treated EAE mice when compared with the MSCs-GFP-treated EAE mice. Inflammatory infiltration and demyelination in the lumbar spinal cord also significantly decreased in the MSCs-IFN β -treated EAE mice compared to PBS- or MSCs-GFP-treated EAE mice. Moreover, MSCs-IFN β treatment enhanced the immunomodulatory effects, which suppressed proinflammatory cytokines (IFN-γ and TNF-α) and conversely increased anti-inflammatory cytokines (IL-4 and IL-10). Importantly, injected MSCs-IFN β migrated into inflamed CNS and significantly reduced further injury of blood-brain barrier (BBB) permeability in EAE mice. Thus, our results provide the rationale for designing novel experimental protocols to enhance the therapeutic effects for MS using hBM-MSCs as an effective gene vehicle to deliver the therapeutic cytokines.
authors.affiliation: Postech-Catholic Biomedical Engineering Institute, Seoul St. Mary's Hospital, The Catholic University of Korea, 505 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea.
authors.forename: Chung Heon
authors.initials: CH
authors.lastname: Ryu
authors.forename: Kwang Ywel
authors.initials: KY
authors.lastname: Park
authors.forename: Yun
authors.initials: Y
authors.lastname: Hou
authors.forename: Chang Hyun
authors.initials: CH
authors.lastname: Jeong
authors.forename: Seong Muk
authors.initials: SM
authors.lastname: Kim
authors.forename: Sin-Soo
authors.initials: SS
authors.lastname: Jeun
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D016899:Interferon-beta / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D016899:Interferon-beta; D007371:Interferon-gamma