Transduction of nonhuman primate brain with adeno-associated virus serotype 1: Vector trafficking and immune response

Piotr Hadaczek, John Forsayeth, Hanna Mirek, Keith Munson, John Bringas, Phil Pivirotto, Jodi McBride, Beverly L. Davidson, Krystof S. Bankiewicz

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

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 mm3 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.

Original languageEnglish (US)
Pages (from-to)225-237
Number of pages13
JournalHuman Gene Therapy
Volume20
Issue number3
DOIs
StatePublished - Mar 1 2009
Externally publishedYes

Fingerprint

Dependovirus
Primates
Brain
Haplorhini
Renilla
Subthalamic Nucleus
Convection
Globus Pallidus
Tropism
Macaca fascicularis
Putamen
Oligodendroglia
Antigen-Presenting Cells
Green Fluorescent Proteins
Transgenes
Reporter Genes
Astrocytes
Genetic Therapy
Serogroup
Anti-Idiotypic Antibodies

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Hadaczek, P., Forsayeth, J., Mirek, H., Munson, K., Bringas, J., Pivirotto, P., ... Bankiewicz, K. S. (2009). Transduction of nonhuman primate brain with adeno-associated virus serotype 1: Vector trafficking and immune response. Human Gene Therapy, 20(3), 225-237. https://doi.org/10.1089/hum.2008.151

Transduction of nonhuman primate brain with adeno-associated virus serotype 1 : Vector trafficking and immune response. / Hadaczek, Piotr; Forsayeth, John; Mirek, Hanna; Munson, Keith; Bringas, John; Pivirotto, Phil; McBride, Jodi; Davidson, Beverly L.; Bankiewicz, Krystof S.

In: Human Gene Therapy, Vol. 20, No. 3, 01.03.2009, p. 225-237.

Research output: Contribution to journalArticle

Hadaczek, P, Forsayeth, J, Mirek, H, Munson, K, Bringas, J, Pivirotto, P, McBride, J, Davidson, BL & Bankiewicz, KS 2009, 'Transduction of nonhuman primate brain with adeno-associated virus serotype 1: Vector trafficking and immune response', Human Gene Therapy, vol. 20, no. 3, pp. 225-237. https://doi.org/10.1089/hum.2008.151
Hadaczek, Piotr ; Forsayeth, John ; Mirek, Hanna ; Munson, Keith ; Bringas, John ; Pivirotto, Phil ; McBride, Jodi ; Davidson, Beverly L. ; Bankiewicz, Krystof S. / Transduction of nonhuman primate brain with adeno-associated virus serotype 1 : Vector trafficking and immune response. In: Human Gene Therapy. 2009 ; Vol. 20, No. 3. pp. 225-237.
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