Recombinant AAV serotype 1 transduction efficiency and tropism in the murine brain

Wang, C.; Wang, C. M.; Clark, K. Reed; Sferra, Thomas J.

doi:10.1038/sj.gt.3302011

Cited by 120 publications

(80 citation statements)

References 39 publications

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“…This positive staining was gradually reduced with new vessel development (k, 3 weeks and l, 5 weeks), suggesting that astrocytes played a supportive role during the neovascularization. In addition, CD31 (m, n) and a-actin finding that neurons and astrocytes are transducible by the recombinant AAV1 vectors (Tenenbaum et al, 2004;Wang et al, 2003). Similar to in vitro studies, the infected cells (neurons and astrocytes) expressed and secreted functional netrin-1 and acted on cells in brain tissue, including endothelial cells.…”

Section: Discussionmentioning

confidence: 59%

Overexpression of Netrin-1 Induces Neovascularization in the Adult Mouse Brain

Fan

Shen

Chen

et al. 2008

J Cereb Blood Flow Metab

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Netrin-1 is a critical molecule for axonal pathfinding during embryo development, and because of its structural homology to the endothelial mitogens, it may share its effects on vascular network formation. Using an adeno-associated viral netrin-1 vector (AAV-NT-1) gene transfer, we demonstrated that netrin-1 was able to stimulate the proliferation and migration of human cerebral endothelial cells (HCECs) and human aortic smooth muscle cells (HASMCs) compared with the control (P < 0.05), and could also promote HCEC tube formation on matrigel (P < 0.05) in vitro. Moreover, netrin-1 hyperstimulation could promote focal neovascularization (P < 0.05) in the adult brain in vivo. Unlike VEGF-induced microvessel increase, netrin-1-induced newly formed vessels showed an artery-like phenotype, with an intact endothelial cell monolayer surrounded by multiple cell layers, including smooth muscle cells and an astrocyte-connected outer layer. Our findings suggest that netrin-1 plays an important role in promoting blood vessel formation in the adult rodent central nervous system, and could have broad implication in cerebrovascular development and remodeling.

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Section: Discussionmentioning

confidence: 59%

Overexpression of Netrin-1 Induces Neovascularization in the Adult Mouse Brain

Fan

Shen

Chen

et al. 2008

J Cereb Blood Flow Metab

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“…In order for such an approach to be clinically effective, it seemed likely that widespread expression in target regions of the brain, cortex, and striatum would be needed. It has been reported that the transduction efficiency in the CNS of AAV1 is superior to that of AAV2 in various animal models, including mouse, rat, and cat (Vite et al, 2003;Wang et al, 2003;Burger et al, 2004). Significantly, however, there is to our knowledge no published report of AAV1 in the primate brain.…”

Section: Introductionmentioning

confidence: 68%

“…A number of reports have shown that the AAV1 serotype transduces the brain more efficiently than does AAV2 (Vite et al, 2003;Wang et al, 2003;Dodge et al, 2005). We have explored in nonhuman primates the utility of this serotype with a vector that encodes a humanized Renilla green fluorescent protein (hrGFP) for which the codon usage has been optimized for use in mammals (see patent WO=2004=005322).…”

Section: Discussionmentioning

confidence: 99%

Transduction of non-human primate brain with adeno-associated virus serotype 1: vector trafficking and immune response

Hadaczek¹,

Forsayeth²,

Mirek³

et al. 2008

Human Gene Therapy

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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 ¼ 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.

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“…AAV2 has shown higher transduction efficiency in glioblastoma in vitro and in vivo when compared to serotypes 4 and 5 [183]. However, other studies have demonstrated a higher distribution and transduction in the CNS when using rAAV serotypes 1 and 5 [175, 184, 185]. The different AAV serotypes have been exploited on their ability to efficiently transduce distinct regions of the brain due to different cellular tropisms [174, 183, 186].…”

Section: Aav Based Vectorsmentioning

confidence: 99%

Herpes Simplex Virus Type 1/Adeno-Associated Virus Hybrid Vectors

Oliveira

Fraefel²

2010

TOVJ

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Herpes simplex virus type 1 (HSV-1) amplicons can accommodate foreign DNA of any size up to 150 kbp and, therefore, allow extensive combinations of genetic elements. Genomic sequences as well as cDNA, large transcriptional regulatory sequences for cell type-specific expression, multiple transgenes, and genetic elements from other viruses to create hybrid vectors may be inserted in a modular fashion. Hybrid amplicons use genetic elements from HSV-1 that allow replication and packaging of the vector DNA into HSV-1 virions, and genetic elements from other viruses that either direct integration of transgene sequences into the host genome or allow episomal maintenance of the vector. Thus, the advantages of the HSV-1 amplicon system, including large transgene capacity, broad host range, strong nuclear localization, and availability of helper virus-free packaging systems are retained and combined with those of heterologous viral elements that confer genetic stability to the vector DNA. Adeno-associated virus (AAV) has the unique capability of integrating its genome into a specific site, designated AAVS1, on human chromosome 19. The AAV rep gene and the inverted terminal repeats (ITRs) that flank the AAV genome are sufficient for this process. HSV-1 amplicons have thus been designed that contain the rep gene and a transgene cassette flanked by AAV ITRs. These HSV/AAV hybrid vectors direct site-specific integration of transgene sequences into AAVS1 and support long-term transgene expression.

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Recombinant AAV serotype 1 transduction efficiency and tropism in the murine brain

Cited by 120 publications

References 39 publications

Overexpression of Netrin-1 Induces Neovascularization in the Adult Mouse Brain

Overexpression of Netrin-1 Induces Neovascularization in the Adult Mouse Brain

Transduction of non-human primate brain with adeno-associated virus serotype 1: vector trafficking and immune response

Herpes Simplex Virus Type 1/Adeno-Associated Virus Hybrid Vectors

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