Neural Stem Cells Engineered to Express Three Therapeutic Factors Mediate Recovery from Chronic Stage CNS Autoimmunity

Li, Xing; Zhang, Yuan; Yan, Yaping; Ciric, Bogoljub; Ma, Cun Gen; Gran, Bruno; Curtis, Mark; Rostami, Abdolmohamad; Zhang, Guang Xian

Abstract

© The American Society of Gene and Cell Therapy. Treatment of chronic neurodegenerative diseases such as multiple sclerosis (MS) remains a major challenge. Here we genetically engineer neural stem cells (NSCs) to produce a triply therapeutic cocktail comprising IL-10, NT-3, and LINGO-1-Fc, thus simultaneously targeting all mechanisms underlie chronicity of MS in the central nervous system (CNS): persistent inflammation, loss of trophic support for oligodendrocytes and neurons, and accumulation of neuroregeneration inhibitors. After transplantation, NSCs migrated into the CNS inflamed foci and delivered these therapeutic molecules in situ. NSCs transduced with one, two, or none of these molecules had no or limited effect when injected at the chronic stage of experimental autoimmune encephalomyelitis; cocktail-producing NSCs, in contrast, mediated the most effective recovery through inducing M2 macrophages/microglia, reducing astrogliosis, and promoting axonal integrity and endogenous oligodendrocyte/neuron differentiation. These engineered NSCs simultaneously target major mechanisms underlying chronicity of multiple sclerosis (MS) and encephalomyelitis (EAE), thus representing a novel and potentially effective therapy for the chronic stage of MS, for which there is currently no treatment available.

Citation

Li, X., Zhang, Y., Yan, Y., Ciric, B., Ma, C. G., Gran, B., …Zhang, G. X. (2016). Neural Stem Cells Engineered to Express Three Therapeutic Factors Mediate Recovery from Chronic Stage CNS Autoimmunity. Molecular Therapy, 24(8), 1456-1469. https://doi.org/10.1038/mt.2016.104

• Journal Article Type: Article
• Acceptance Date: Apr 25, 2016
• Online Publication Date: Dec 14, 2016
• Publication Date: 2016-08
• Deposit Date: Sep 29, 2020
• Publicly Available Date: Oct 2, 2020
• Journal: Molecular Therapy
• Print ISSN: 1525-0016
• Electronic ISSN: 1525-0024
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 24
• Issue: 8
• Pages: 1456-1469
• DOI: https://doi.org/10.1038/mt.2016.104
• Public URL: https://nottingham-repository.worktribe.com/output/3227372
• Publisher URL: https://doi.org/10.1038/mt.2016.104
• Related Public URLs: https://www.sciencedirect.com/science/article/pii/S1525001616335973