title: A brain microvasculature endothelial cell-specific viral vector with the potential to treat neurovascular and neurological diseases.
abstract: Gene therapy critically relies on vectors that combine high transduction efficiency with a high degree of target specificity and that can be administered through a safe intravenous route. The lack of suitable vectors, especially for gene therapy of brain disorders, represents a major obstacle. Therefore, we applied an in vivo screening system of random ligand libraries displayed on adeno-associated viral capsids to select brain-targeted vectors for the treatment of neurovascular diseases. We identified a capsid variant showing an unprecedented degree of specificity and long-lasting transduction efficiency for brain microvasculature endothelial cells as the primary target of selection. A therapeutic vector based on this selected viral capsid was used to markedly attenuate the severe cerebrovascular pathology of mice with incontinentia pigmenti after a single intravenous injection. Furthermore, the versatility of this selection system will make it possible to select ligands for additional in vivo targets without requiring previous identification of potential target-specific receptors.
authors.affiliation: Hubertus Wald Cancer Center, Department of Oncology and Hematology University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Körbelin
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
authors.forename: Godwin
authors.initials: G
authors.lastname: Dogbevia
authors.affiliation: Hubertus Wald Cancer Center, Department of Oncology and Hematology University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Michelfelder
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Ridder
authors.affiliation: Hubertus Wald Cancer Center, Department of Oncology and Hematology University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Agnes
authors.initials: A
authors.lastname: Hunger
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Wenzel
authors.affiliation: Hubertus Wald Cancer Center, Department of Oncology and Hematology University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Seismann
authors.affiliation: Hubertus Wald Cancer Center, Department of Oncology and Hematology University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Lampe
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bannach
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC), Institute for Genetics University of Cologne, Cologne, Germany.
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.affiliation: Department of Tumor Virology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Jürgen A
authors.initials: JA
authors.lastname: Kleinschmidt
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaninger
authors.affiliation: Hubertus Wald Cancer Center, Department of Oncology and Hematology University Medical Center Hamburg-Eppendorf, Hamburg, Germany Department of Hematology and Oncology, Augsburg Medical Center, Augsburg, Germany m.trepel@uke.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Trepel
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007184:Incontinentia Pigmenti / Q000628:therapy*; D007275:Injections, Intravenous; D051379:Mice; D055806:Microvessels / Q000473:pathology*; D014161:Transduction, Genetic; D016896:Treatment Outcome
keywords: adeno‐associated virus; brain microvascular endothelial cells; gene therapy; neurovascular diseases