Mifepristone-inducible transgene expression in neural progenitor cells in vitro and in vivo

• Published in: Gene therapy 2016-05, Vol.23 (5), p.424-437
• Main Authors: Hjelm, B E, Grunseich, C, Gowing, G, Avalos, P, Tian, J, Shelley, B C, Mooney, M, Narwani, K, Shi, Y, Svendsen, C N, Wolfe, J H, Fischbeck, K H, Pierson, T M
• Format: Article
• Language: English
• Subjects: 13/100; 13/31; 13/51; 14/1; 14/63; 38/23; 38/39; 38/44; 42/35; 631/378/2571/2579; 692/699/375; 692/699/375/365; 692/700/565/201; Analysis; Animal models; Animals; Biomedical and Life Sciences; Biomedicine; Blood-brain barrier; Blood-Brain Barrier - drug effects; Care and treatment; Cell Biology; Cell therapy; Cell- and Tissue-Based Therapy; Central nervous system; Central Nervous System - drug effects; Central Nervous System - pathology; Gene Expression; Gene Expression Regulation - drug effects; Gene Therapy; Genetic aspects; Genetic research; Genetic Therapy; Genetic Vectors; Health aspects; Human Genetics; Humans; Innovations; Lentivirus - genetics; Ligands; Mice; Mifepristone; Mifepristone - pharmacology; Molecular targeted therapy; Nanotechnology; Nervous system; Nervous system diseases; Neural stem cells; Neural Stem Cells - transplantation; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - therapy; Neurological diseases; Neurons; Observations; original-article; Patient outcomes; Progenitor cells; Stem Cell Transplantation; Stem Cells; Transgenes; Transgenes - genetics
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2016.13

Numerous gene and cell therapy strategies are being developed for the treatment of neurodegenerative disorders. Many of these strategies use constitutive expression of therapeutic transgenic proteins, and although functional in animal models of disease, this method is less likely to provide adequate flexibility for delivering therapy to humans. Ligand-inducible gene expression systems may be more appropriate for these conditions, especially within the central nervous system (CNS). Mifepristone’s ability to cross the blood–brain barrier makes it an especially attractive ligand for this purpose. We describe the production of a mifepristone-inducible vector system for regulated expression of transgenes within the CNS. Our inducible system used a lentivirus-based vector platform for the ex vivo production of mifepristone-inducible murine neural progenitor cells that express our transgenes of interest. These cells were processed through a series of selection steps to ensure that the cells exhibited appropriate transgene expression in a dose-dependent and temporally controlled manner with minimal background activity. Inducible cells were then transplanted into the brains of rodents, where they exhibited appropriate mifepristone-inducible expression. These studies detail a strategy for regulated expression in the CNS for use in the development of safe and efficient gene therapy for neurological disorders.