title: Mifepristone-inducible transgene expression in neural progenitor cells in vitro and in vivo.
abstract: 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.
authors: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: B E
authors: BE
authors: Hjelm
authors: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
authors: C
authors: C
authors: Grunseich
authors: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: G
authors: G
authors: Gowing
authors: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: P
authors: P
authors: Avalos
authors: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: J
authors: J
authors: Tian
authors: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: B C
authors: BC
authors: Shelley
authors: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
authors: M
authors: M
authors: Mooney
authors: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: K
authors: K
authors: Narwani
authors: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
authors: Y
authors: Y
authors: Shi
authors: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: C N
authors: CN
authors: Svendsen
authors: Departments of Pediatrics and Pathobiology, University of Pennsylvania, Philadelphia, PA, USA.|Stokes Research Institute, Children's Hospital of Philadelphia, PA, USA.
authors: J H
authors: JH
authors: Wolfe
authors: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
authors: K H
authors: KH
authors: Fischbeck
authors: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Department of Pediatrics and Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: T M
authors: TM
authors: Pierson
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy; D002490:Central Nervous System / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D058953:Neural Stem Cells / Q000637:transplantation*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000628:therapy*; D033581:Stem Cell Transplantation; D013234:Stem Cells; D019076:Transgenes / Q000235:genetics
chemical_list: D015735:Mifepristone