Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery

Abstract

The direct intraparenchymal administration of oncolytic viral vectors by convection-enhanced delivery (CED) represents a promising new treatment strategy for malignant gliomas. However, there is no evidence to suggest that oncolytic viruses as large as herpes simplex virus-1 (HSV-1) can be administered by CED, as this has not been systematically examined in an animal model. In this study, the administration of a herpes simplex viral vector, HSV1, has been evaluated in detail in the gray and white matter of both rat and pig models, using high flow-rate infusions, co-infusing heparin or preinfusing the tissue with an isotonic albumin solution. Rat HSV-1 infusions at both slow (0.5 ml min À1 ) and high infusion rates (2.5 ml min À1 ) led to extensive tissue damage and negligible cell transduction. Co-infusion with heparin led to extensive hemorrhage. Preinfusion of tissue with an isotonic albumin solution facilitated widespread vector distribution and cell transduction in white matter only. Using this approach in pig brain led to widespread vector distribution with extensive transduction of astrocytes and activated microglia. In rat brain, enhanced green fluorescent protein expression peaked 48 h after vector administration and was associated with a vigorous immune response. These findings indicate that direct infusions of HSV-1-based viral vectors into the brain lead to minimal vector distribution, negligible cell transduction and extensive damage. Tissue preinfusion with an isotonic solution prior to vector administration represents an effective technique for achieving widespread HSV-1 distribution.

Cell Division Modes and Cleavage Planes of Neural Progenitors during Mammalian Cortical Development

“…The second transition allows the RGs in the VZ to adapt to a different niche, the outer SVZ. Indeed, the number of o/bRG cells is correlated with the degree of gyration (e.g., humans, monkeys, and ferrets), suggesting (Lui et al 2011;Reillo et al 2011;White et al 2011) that the new niche, where the self-renewing progenitors reside after the second transition, may contribute to the increased proliferative capacity of o/bRG cells in mammalian species. Thus, the second transition of the division mode from RG cells to o/bRG cells may be key to the evolution of mammalian brain size.…”

Lipid peptide nanocomplexes for gene delivery and magnetic resonance imaging in the brain

“…Brain sectioning, and immunofluorescence staining for microglial cells with mouse anti-ED1 (1:100; Serotec, UK) were performed as described previously [14]. All microscopic images were obtained using a Leica DM5500 microscope and digital camera (MBF, Germany).…”

The art of gene therapy for glioma: a review of the challenging road to the bedside

“…92 Convection-enhanced delivery Achieve high virus/vector concentrations over large volumes of targeted tissue; enhanced levels of transduction. 93 Next generation OV vectors Increased vector penetration and transduction efficiency. 62 3.…”