Abstract
Gene therapy represents a promising approach for the treatment of monogenic and multifactorial neurological disorders. It can be used to replace a missing gene and mutated gene or downregulate a causal gene. Despite the versatility of gene therapy, one of the main limitations lies in the irreversibility of the process: once delivered to target cells, the gene of interest is constitutively expressed and cannot be removed. Therefore, efficient, safe and long-term gene modification requires a system allowing fine control of transgene expression.
Different systems have been developed over the past decades to regulate transgene expression after in vivo delivery, either at transcriptional or post-translational levels. The purpose of this chapter is to give an overview on current regulatory system used in the context of gene therapy for neurological disorders. Systems using external regulation of transgenes using antibiotics are commonly used to control either gene expression using tetracycline-controlled transcription or protein levels using destabilizing domain technology. Alternatively, specific promoters of genes that are regulated by disease mechanisms, increasing expression as the disease progresses or decreasing expression as disease regresses, are also examined. Overall, this chapter discusses advantages and drawbacks of current molecular methods for regulated gene therapy in the central nervous system.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsSpringer Nature is developing a new tool to find and evaluate Protocols. Learn more
References
Cress D. E. (2008) The need for regulatable vectors for gene therapy for Parkinson’s disease. Exp Neurol 209:30–3
Kordower J. H. and Olanow C. W. (2008) Regulatable promoters and gene therapy for Parkinson’s disease: is the only thing to fear, fear itself? Exp Neurol 209:34–40
Gossen M, Bujard H (1992) Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci U S A 89:5547–5551
Gossen M, Freundlieb S, Bender G et al (1995) Transcriptional activation by tetracyclines in mammalian cells. Science 268:1766–1769
Cunha BA (2000) Minocycline versus doxycycline in the treatment of Lyme neuroborreliosis. Clin Infect Dis 30:237–238
Penttila O, Neuvonen PJ, Aho K et al (1974) Interaction between doxycycline and some antiepileptic drugs. Br Med J 2:470–472
Okoye G, Zimmer J, Sung J et al (2003) Increased expression of brain-derived neurotrophic factor preserves retinal function and slows cell death from rhodopsin mutation or oxidative damage. J Neurosci 23:4164–4172
Kafri T, van Praag H, Gage FH et al (2000) Lentiviral vectors: regulated gene expression. Mol Ther 1:516–521
Corti O, Sanchez-Capelo A, Colin P et al (1999) Long-term doxycycline-controlled expression of human tyrosine hydroxylase after direct adenovirus-mediated gene transfer to a rat model of Parkinson’s disease. Proc Natl Acad Sci U S A 96:12120–12125
Gonzalez-Zorn B, Escudero JA (2012) Ecology of antimicrobial resistance: humans, animals, food and environment. Int Microbiol 15:101–109
Naidoo J, Young D (2012) Gene regulation systems for gene therapy applications in the central nervous system. Neurol Res Int 2012:595410
Xu F, Sternberg MR, Kottiri BJ et al (2006) Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA 296:964–973
Jakobsson J, Rosenqvist N, Marild K et al (2006) Evidence for disease-regulated transgene expression in the brain with use of lentiviral vectors. J Neurosci Res 84:58–67
Shen F, Fan Y, Su H et al (2008) Adeno-associated viral vector-mediated hypoxia-regulated VEGF gene transfer promotes angiogenesis following focal cerebral ischemia in mice. Gene Ther 15:30–39
Greenberg DA, Jin K (2005) From angiogenesis to neuropathology. Nature 438:954–959
Liu Y, Figley S, Spratt SK et al (2010) An engineered transcription factor which activates VEGF-A enhances recovery after spinal cord injury. Neurobiol Dis 37:384–393
Siddiq I, Park E, Liu E et al (2012) Treatment of traumatic brain injury using zinc-finger protein gene therapy targeting VEGF-A. J Neurotrauma 29:2647–2659
D’Onofrio PM, Thayapararajah M, Lysko MD et al (2011) Gene therapy for traumatic central nervous system injury and stroke using an engineered zinc finger protein that upregulates VEGF-A. J Neurotrauma 28:1863–1879
Garriga-Canut M, Agustin-Pavon C, Herrmann F et al (2012) Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice. Proc Natl Acad Sci U S A 109:E3136–E3145
Laganiere J, Kells AP, Lai JT et al (2010) An engineered zinc finger protein activator of the endogenous glial cell line-derived neurotrophic factor gene provides functional neuroprotection in a rat model of Parkinson’s disease. J Neurosci 30:16469–16474
Konermann S, Brigham MD, Trevino AE et al (2013) Optical control of mammalian endogenous transcription and epigenetic states. Nature 500:472–476
Rebar EJ, Huang Y, Hickey R et al (2002) Induction of angiogenesis in a mouse model using engineered transcription factors. Nat Med 8:1427–1432
Banaszynski LA, Chen LC, Maynard-Smith LA et al (2006) A rapid, reversible, and tunable method to regulate protein function in living cells using synthetic small molecules. Cell 126:995–1004
Iwamoto M, Bjorklund T, Lundberg C et al (2010) A general chemical method to regulate protein stability in the mammalian central nervous system. Chem Biol 17:981–988
Miyazaki Y, Imoto H, Chen LC et al (2012) Destabilizing domains derived from the human estrogen receptor. J Am Chem Soc 134:3942–3945
Tu YH, Allen LV Jr, Fiorica VM et al (1989) Pharmacokinetics of trimethoprim in the rat. J Pharm Sci 78:556–560
Hayashi S, McMahon AP (2002) Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev Biol 244:305–318
Tai K, Quintino L, Isaksson C et al (2012) Destabilizing domains mediate reversible transgene expression in the brain. PLoS One 7:e46269
Quintino L, Manfre G, Wettergren EE et al (2013) Functional neuroprotection and efficient regulation of GDNF using destabilizing domains in a rodent model of Parkinson’s disease. Mol Ther 21:2169–2180
Sellmyer MA, Chen LC, Egeler EL et al (2012) Intracellular context affects levels of a chemically dependent destabilizing domain. PLoS One 7:e43297
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer Science+Business Media New York
About this protocol
Cite this protocol
Breger, L., Wettergren, E.E., Quintino, L., Lundberg, C. (2016). Regulated Gene Therapy. In: Manfredsson, F. (eds) Gene Therapy for Neurological Disorders. Methods in Molecular Biology, vol 1382. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3271-9_4
Download citation
DOI: https://doi.org/10.1007/978-1-4939-3271-9_4
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-3270-2
Online ISBN: 978-1-4939-3271-9
eBook Packages: Springer Protocols