title: Regulated Gene Therapy.
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.
authors.affiliation: Department of Experimental Medical Sciences, CNS Gene Therapy Unit, Wallenberg Neuroscience Center, Lund University, BMC A11, 221 84, Lund, Sweden.
authors.forename: Ludivine
authors.initials: L
authors.lastname: Breger
authors.affiliation: Department of Experimental Medical Sciences, CNS Gene Therapy Unit, Wallenberg Neuroscience Center, Lund University, BMC A11, 221 84, Lund, Sweden.
authors.forename: Erika Elgstrand
authors.initials: EE
authors.lastname: Wettergren
authors.affiliation: Department of Experimental Medical Sciences, CNS Gene Therapy Unit, Wallenberg Neuroscience Center, Lund University, BMC A11, 221 84, Lund, Sweden.
authors.forename: Luis
authors.initials: L
authors.lastname: Quintino
authors.affiliation: Department of Experimental Medical Sciences, CNS Gene Therapy Unit, Wallenberg Neuroscience Center, Lund University, BMC A11, 221 84, Lund, Sweden. Cecilia.Lundberg@med.lu.se.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lundberg
mesh_terms: D005786:Gene Expression Regulation; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D009422:Nervous System Diseases / Q000628:therapy; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000378:metabolism; D019076:Transgenes
chemical_list: D015534:Trans-Activators
keywords: Destabilizing domain; Doxycycline; Promoter; Tet-responsive; Trimethoprim; Zinc finger-based transcription factor