AAV9-mediated Expression of a Non-self Protein in Nonhuman Primate Central Nervous System Triggers Widespread Neuroinflammation Driven by Antigen-presenting Cell Transduction

Many studies have demonstrated that adeno-associated virus serotype 9 (AAV9) transduces astrocytes and neurons when infused into rat or nonhuman primate (NHP) brain. We previously showed in rats that transduction of antigen-presenting cells (APC) by AAV9 encoding a foreign protein triggered a full n...

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Bibliographic Details
Published in:Molecular therapy 2014-02, Vol.22 (2), p.329-337
Main Authors: Samaranch, Lluis, Sebastian, Waldy San, Kells, Adrian P, Salegio, Ernesto A, Heller, Gregory, Bringas, John R, Pivirotto, Philip, DeArmond, Stephen, Forsayeth, John, Bankiewicz, Krystof S
Format: Article
Language:English
Subjects:
Adeno-associated virus
Amino acids
Animals
Antibodies
Antigen-Presenting Cells - immunology
Antigen-Presenting Cells - metabolism
Antigens
Brain
Central Nervous System - immunology
Central Nervous System - metabolism
Central Nervous System - pathology
Corpus Striatum - immunology
Corpus Striatum - metabolism
Corpus Striatum - pathology
Cytotoxicity
Dependovirus - genetics
Dependovirus - immunology
Gene Expression
Gene therapy
Genes, Reporter
Genetic Vectors - administration & dosage
Genetic Vectors - genetics
Genetic Vectors - immunology
Green Fluorescent Proteins - genetics
Humans
Inflammation - genetics
Inflammation - immunology
Inflammation - pathology
Magnetic resonance imaging
Monkeys & apes
Nervous system
Neurons
Neurons - metabolism
Neurons - pathology
Neurotoxicity
Original
Proteins
Rats
Surgery
Toxicology
Transduction, Genetic
Transgenes
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Summary:Many studies have demonstrated that adeno-associated virus serotype 9 (AAV9) transduces astrocytes and neurons when infused into rat or nonhuman primate (NHP) brain. We previously showed in rats that transduction of antigen-presenting cells (APC) by AAV9 encoding a foreign protein triggered a full neurotoxic immune response. Accordingly, we asked whether this phenomenon occurred in NHP. We performed parenchymal or intrathecal infusion of AAV9 encoding green fluorescent protein (GFP), a non-self protein derived from jellyfish, or human aromatic L-amino acid decarboxylase (hAADC), a self-protein, in separate NHP. Animals receiving AAV9-GFP into cisterna magna (CM) became ataxic, indicating cerebellar pathology, whereas AAV9-hAADC animals remained healthy. In transduced regions, AAV9-GFP elicited inflammation associated with early activation of astrocytic and microglial cells, along with upregulation of major histocompatibility complex class II (MHC-II) in glia. In addition, we found Purkinje neurons lacking calbindin after AAV9-GFP but not after AAV9-hAADC delivery. Our results demonstrate that AAV9-mediated expression of a foreign-protein, but not self-recognized protein, triggers complete immune responses in NHP regardless of the route of administration. Our results warrant caution when contemplating use of serotypes that can transduce APC if the transgene is not syngeneic with the host. This finding has the potential to complicate preclinical toxicology studies in which such vectors encoding human cDNA's are tested in animals.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2013.266