title: Adeno-Associated Viral Vectors Serotype 8 for Cell-Specific Delivery of Therapeutic Genes in the Central Nervous System.
abstract: Adeno-associated viruses (AAVs) have become highly promising tools for research and clinical applications in the central nervous system (CNS). However, specific delivery of genes to the cell type of interest is essential for the success of gene therapy and therefore a correct selection of the promoter plays a very important role. Here, AAV8 vectors carrying enhanced green fluorescent protein (eGFP) as reporter gene under the transcriptional control of different CNS-specific promoters were used and compared with a strong ubiquitous promoter. Since one of the main limitations of AAV-mediated gene delivery lies in its restricted cloning capacity, we focused our work on small-sized promoters. We tested the transduction efficacy and specificity of each vector after stereotactic injection into the mouse striatum. Three glia-specific AAV vectors were generated using two truncated forms of the human promoter for glial fibrillar acidic protein (GFAP) as well as a truncated form of the murine GFAP promoter. All three vectors resulted in predominantly glial expression; however we also observed eGFP expression in other cell-types such as oligodendrocytes, but never in neurons. In addition, robust and neuron-specific eGFP expression was observed using the minimal promoters for the neural protein BM88 and the neuronal nicotinic receptor β2 (CHRNB2). In summary, we developed a set of AAV vectors designed for specific expression in cells of the CNS using minimal promoters to drive gene expression when the size of the therapeutic gene matters.
authors.affiliation: Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical ResearchPamplona, Spain; Department of Neurosciences, Center for Applied Medical ResearchPamplona, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Pignataro
authors.affiliation: Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical ResearchPamplona, Spain; Department of Neurosciences, Center for Applied Medical ResearchPamplona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades NeurodegenerativasSpain.
authors.forename: Diego
authors.initials: D
authors.lastname: Sucunza
authors.affiliation: Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical Research Pamplona, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Vanrell
authors.affiliation: Department of Neurosciences, Center for Applied Medical Research Pamplona, Spain.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Lopez-Franco
authors.affiliation: Department of Neurosciences, Center for Applied Medical ResearchPamplona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades NeurodegenerativasSpain; Instituto de Investigación Sanitaria de NavarraPamplona, Spain.
authors.forename: Iria G
authors.initials: IG
authors.lastname: Dopeso-Reyes
authors.affiliation: Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical Research Pamplona, Spain.
authors.forename: Africa
authors.initials: A
authors.lastname: Vales
authors.affiliation: Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical ResearchPamplona, Spain; Instituto de Investigación Sanitaria de NavarraPamplona, Spain.
authors.forename: Mirja
authors.initials: M
authors.lastname: Hommel
authors.affiliation: Department of Neurosciences, Center for Applied Medical ResearchPamplona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades NeurodegenerativasSpain; Instituto de Investigación Sanitaria de NavarraPamplona, Spain.
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Rico
authors.affiliation: Department of Neurosciences, Center for Applied Medical ResearchPamplona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades NeurodegenerativasSpain; Instituto de Investigación Sanitaria de NavarraPamplona, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Lanciego
authors.affiliation: Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical ResearchPamplona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades NeurodegenerativasSpain; Instituto de Investigación Sanitaria de NavarraPamplona, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Gonzalez-Aseguinolaza
keywords: AAV; CNS; Parkinson's disease; basal ganglia; gene therapy; promoters