Adeno‐associated virus (AAV) serotypes 2, 4 and 5 display similar transduction profiles and penetrate solid tumor tissue in models of human glioma

Thorsen, Frits; Afione, Sandra; Huszthy, Peter C.; Tysnes, Berit Bølge; Svendsen, Agnete; Bjerkvig, Rolf; Kotin, Robert M.; Lønning, Per Eystein; Hoover, Frank

doi:10.1002/jgm.939

Cited by 20 publications

(17 citation statements)

References 57 publications

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“…20 Direct transplantation of such 'organotypic' spheroids into rodent brains forms lesions that eventually recapitulate all the histopathological hallmarks of GBM in situ, such as extensive single-cell infiltration, angiogenesis the occurrence of necroses with palisading tumor cells, endothelial proliferations and dilated, thrombotic vessels. 18,21 We have recently used this model to evaluate gene transfer to human GBM cells 22,23 as well as to study the biological aspects of tumor cell invasion. 24 Since the described model reflects the key features of human glioma progression, we chose to assess the effect of G207 on a set of xenograft phenotypes that follow these biological features.…”

Section: Introductionmentioning

confidence: 99%

Cellular effects of oncolytic viral therapy on the glioblastoma microenvironment

et al. 2009

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The objective of the present study was to evaluate the cellular effects of the oncolytic HSV-1 based vector, G207, on the tumor microenvironment. We established progressively growing intracerebral xenografts in athymic nude rats generated from three different human GBM surgical specimens. The lesions were identified by MRI and subsequently injected with a concentrated vector stock. The animals were killed 10 or 30 days after G207 injection and the tumors were quantitatively evaluated for virus-induced changes in proliferation, apoptosis and vascularity. Moreover, we assessed vector spread as well as the infiltration pattern of CD68-positive inflammatory cells. In all G207-injected lesions, immunostaining identified widespread regions of viral infection and replication (plaques). Proliferation indices were significantly lower, whereas apoptotic counts were significantly elevated in plaques as compared with that in non-infected areas of the same lesions, as well as in corresponding control xenografts. Furthermore, there was a significant decline in the number of blood vessels in the plaques and the vascular area fractions were reduced. CD68-positive inflammatory cells accumulated in the plaques. The present study highlights the favorable cellular responses to G207 treatment seen from a clinical viewpoint, such as reduced tumor cell proliferation, more frequent events of tumor cell death and a strongly attenuated tumor vascular compartment. However, our results suggest that transduction of a significant volume of tumor tissue is essential, as these beneficial changes were only observed in areas of active viral replication, leaving non-transduced tumor tissues unaffected.

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Section: Introductionmentioning

confidence: 99%

Cellular effects of oncolytic viral therapy on the glioblastoma microenvironment

et al. 2009

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“…To overcome this obstacle, significant progress in virology may come to help: researchers are currently studying novel gene delivery methods and in this context recombinant adenoassociated viruses may serve as low immunogenic and cellor tissue-specific vectors. Already the proof of the principle has been delivered in experiments with adeno-associated viruses which penetrate solid tumor tissue [122] and it is to be expected that these tailored viruses can be used as a platform for advanced drug and imaging nanotechnology [123]. Furthermore, double action can be achieved by combining oncolytic viruses with preferential replication in tumor cells with drug containing nanoparticles [124].…”

Section: Antibody-based Targetingmentioning

confidence: 99%

Ligand-based targeted therapy for cancer tissue

Das

Mohanty

Sahoo

2009

Expert Opinion on Drug Delivery

210

123

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“…AAV2 has been the most widely used AAV serotype for gene delivery to the CNS, transducing almost exclusively neurons in different brain structures [175-178], and supporting long-term transgene expression in the CNS [179-181] as well as in the dorsal root ganglia [182]. 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].…”

Section: Aav Based Vectorsmentioning

confidence: 99%

“…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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Adeno‐associated virus (AAV) serotypes 2, 4 and 5 display similar transduction profiles and penetrate solid tumor tissue in models of human glioma

Cited by 20 publications

References 57 publications

Cellular effects of oncolytic viral therapy on the glioblastoma microenvironment

Cellular effects of oncolytic viral therapy on the glioblastoma microenvironment

Ligand-based targeted therapy for cancer tissue

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

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