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Controlling brain tumor growth by intraventricular administration of an AAV vector encoding IFN-beta.

ABSTRACT: Glioblastoma multiforme (GBM) is the most aggressive type of all primary brain tumors, with an overall median survival <1 year after diagnosis. Despite introduction of multimodal treatment approaches, the prognosis has not improved significantly over the past 50 years. In this study we investigated the effect of intracerebroventricular (ICV) injection of an adeno-associated virus (AAV) vector encoding human interferon-beta (AAV-hIFN-beta) on glioblastoma growth. Recently, we found that peritumoral parenchymal transduction with an AAV-hIFN-beta was exceptionally efficient in eradicating GBM brain tumors. However, the extensive infiltration and migration displayed by glioblastoma cells in patients may leave a significant number of tumor cells outside a local therapeutic zone created by intraparenchymal delivery of AAV vectors. Here we show that pretreatment of mice by ICV infusion of an AAV-IFN-beta completely prevents tumor growth in an orthotopic model of GBM. Furthermore, ICV infusion of AAV-IFN-beta into mice bearing preestablished U87 intracranial tumors improved their survival compared to mice infused through the same route with a control AAV vector. These data suggest that ICV injection of AAV vectors encoding antitumor proteins is a promising approach deserving further consideration for the treatment of GBM.

SUBMITTER: Meijer DH

PROVIDER: S-EPMC2946391 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Controlling brain tumor growth by intraventricular administration of an AAV vector encoding IFN-beta.

Meijer D H DH Maguire C A CA LeRoy S G SG Sena-Esteves M M

Cancer gene therapy 20090206 8

Glioblastoma multiforme (GBM) is the most aggressive type of all primary brain tumors, with an overall median survival <1 year after diagnosis. Despite introduction of multimodal treatment approaches, the prognosis has not improved significantly over the past 50 years. In this study we investigated the effect of intracerebroventricular (ICV) injection of an adeno-associated virus (AAV) vector encoding human interferon-beta (AAV-hIFN-beta) on glioblastoma growth. Recently, we found that peritumor ...[more]

PMID: 19197327

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Project description:BackgroundTargeted delivery of gene therapy vectors to the mouse respiratory tract is often performed via intranasal or intratracheal administration; however, there can be a great deal of variability between these methods, which could potentially influence experimental results. Improving the accuracy and precision of lung delivery will not only reduce the number of animals required to detect statistically significant differences, but may reduce the variability of studies from different laboratories.ResultsHere we evaluated three different methods of adeno-associated virus (AAV) vector administration to the respiratory tract in mice (intranasal, intubation, and intratracheal injection) and discuss the advantages, challenges, and shortcomings of each. We also present a modified-intranasal delivery technique that is superior to passive administration of vector into the nares of anesthetized supine animals. Transgene expression was consistently visible in the nasal cavity, trachea, and proximal to middle aspect of all lung lobes for all four methods, whereas transgene expression was consistently observed in the most distal aspect of lung lobes only with the intubation and intratracheal injection techniques. AAV vector genome copy numbers in the lung were approximately four-fold lower in mice that received vector via intranasal administration in comparison to the other three methods of vector delivery. The modified intranasal, intubation and intratracheal injection methods of vector administration did not yield statistical differences in AAV vector genome copy numbers in the lung. With regard to reproducibility of vector distribution within and between animals, the modified-intranasal technique was superior.ConclusionOur results show that mode of AAV vector administration to the murine respiratory tract should be selected based on desired target site and skill of the researcher, and that appropriate technique selection may greatly influence experimental outcomes.

Dataset Information

Controlling brain tumor growth by intraventricular administration of an AAV vector encoding IFN-beta.

Publications

Controlling brain tumor growth by intraventricular administration of an AAV vector encoding IFN-beta.

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