Transduction of non-human primate brain with adeno-associated virus serotype 1: vector trafficking and immune response
| Autor: | Piotr Hadaczek, John Forsayeth, Krystof S. Bankiewicz, Keith Munson, Jodi L. McBride, Phil Pivirotto, Beverly L. Davidson, Hanna Mirek, John Bringas |
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| Rok vydání: | 2008 |
| Předmět: |
Scientific Articles
endocrine system Genetic Vectors Green Fluorescent Proteins Central nervous system Striatum Biology Pharmacology Gene delivery medicine.disease_cause Green fluorescent protein Prosencephalon Transduction Genetic medicine Genetics Animals Humans Infusions Parenteral Adeno-associated virus Molecular Biology Neurons Basal forebrain Putamen Genetic Therapy Dependovirus Virology Recombinant Proteins Macaca fascicularis Oligodendroglia Subthalamic nucleus medicine.anatomical_structure nervous system Astrocytes Antibody Formation Molecular Medicine Nervous System Diseases |
| Zdroj: | Human Gene Therapy. :081212071307053 |
| ISSN: | 1557-7422 1043-0342 |
| DOI: | 10.1089/hgt.2008.151 |
| Popis: | We used convection-enhanced delivery (CED) to characterize gene delivery mediated by adeno-associated virus type 1 (AAV1) by tracking expression of hrGFP (humanized green fluorescent protein from Renilla reniformis) into the striatum, basal forebrain, and corona radiata of monkey brain. Four cynomolgus monkeys received single infusions into corona radiata, putamen, and caudate. The other group (n = 4) received infusions into basal forebrain. Thirty days after infusion animals were killed and their brains were processed for immunohistochemical evaluation. Volumetric analysis of GFP-positive brain areas was performed. AAV1-hrGFP infusions resulted in approximately 550, 700, and 73 mm(3) coverage after infusion into corona radiata, striatum, and basal forebrain, respectively. Aside from targeted regions, other brain structures also showed GFP signal (internal and external globus pallidus, subthalamic nucleus), supporting the idea that AAV1 is actively trafficked to regions distal from the infusion site. In addition to neuronal transduction, a significant nonneuronal cell population was transduced by AAV1 vector; for example, oligodendrocytes in corona radiata and astrocytes in the striatum. We observed a strong humoral and cell-mediated response against AAV1-hrGFP in transduced monkeys irrespective of the anatomic location of the infusion, as evidenced by induction of circulating anti-AAV1 and anti-hrGFP antibodies, as well as infiltration of CD4(+) lymphocytes and upregulation of MHC-II in regions infused with vector. We conclude that transduction of antigen-presenting cells within the CNS is a likely cause of this response and that caution is warranted when foreign transgenes are used as reporters in gene therapy studies with vectors with broader tropism than AAV2. |
| Databáze: | OpenAIRE |
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