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

Mol Ther. 2016 Aug;24(8):1456-69. doi: 10.1038/mt.2016.104. Epub 2016 May 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autoimmunity*
  • Cell Differentiation
  • Cell Engineering*
  • Cell Proliferation
  • Disease Models, Animal
  • Disease Progression
  • Encephalomyelitis, Autoimmune, Experimental / diagnosis
  • Encephalomyelitis, Autoimmune, Experimental / genetics*
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / therapy
  • Female
  • Gene Expression*
  • Genetic Vectors / genetics
  • Interleukin-10 / genetics
  • Lentivirus / genetics
  • Macrophages / metabolism
  • Mice
  • Microglia / metabolism
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / pathology
  • Multiple Sclerosis / therapy
  • Myelin Basic Protein / biosynthesis
  • Myelin Proteins / metabolism
  • Nerve Growth Factors / genetics
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism*
  • Neurons / metabolism
  • Neurons / pathology
  • Oligodendroglia / cytology
  • Oligodendroglia / metabolism
  • Stem Cell Transplantation
  • Transduction, Genetic
  • Transgenes*


  • Myelin Basic Protein
  • Myelin Proteins
  • Nerve Growth Factors
  • Interleukin-10