title: Intracerebroventricular injection of adeno-associated virus 6 and 9 vectors for cell type-specific transgene expression in the spinal cord.
abstract: In the context of motoneuron diseases, gene delivery as an experimental or therapeutic approach is hindered by the challenge to specifically target cell populations that are widely distributed along the spinal cord. Further complicating the task, transgenes often need to be delivered to motoneurons and/or glial cells to address the non-cell-autonomous mechanisms involved in disease pathogenesis. Intracerebroventricular (ICV) injection of recombinant adeno-associated viruses (AAVs) in newborn mice allows distributing viral vectors throughout the central nervous system while limiting undesired transduction of peripheral organs. Here, we show that by combining the appropriate set of AAV serotype and promoter, specific transgene expression can be achieved in either motoneurons or astrocytes along the whole mouse spinal cord. ICV injection of recombinant AAV6 with the cytomegalovirus (cmv) promoter preferentially targets motoneurons, whereas AAV9 particles combined with the astrocyte-specific gfaABC₁D promoter lead to significant transgene expression selectively targeted to astrocytes. Importantly, ICV coinjection of both AAV6-cmv and AAV9-gfaABC₁D results in segregated expression of two different transgenes in motoneurons and astrocytes, respectively. Relevance of viral vector delivery via the cerebrospinal fluid was further investigated in young nonhuman primates. Intracisternal injection of recombinant AAV6-cmv led to robust cervical transduction of motoneurons, highlighting the potential of this approach for gene therapy and modeling of motoneuron diseases.
authors.affiliation: 1 Brain Mind Institute , Ecole Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland .
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Dirren
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Towne
authors.forename: Veronica
authors.initials: V
authors.lastname: Setola
authors.forename: Donald E
authors.initials: DE
authors.lastname: Redmond
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Schneider
authors.forename: Patrick
authors.initials: P
authors.lastname: Aebischer
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002522:Chlorocebus aethiops; D000229:Dependovirus / Q000235:genetics*; D018628:Gene Dosage; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D013116:Spinal Cord / Q000378:metabolism*; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D049452:Green Fluorescent Proteins