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 μl min−1) and high infusion rates (2.5 μl min−1) 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.
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Wrensch M, Minn Y, Chew T, Bondy M, Berger MS . Epidemiology of primary brain tumors: current concepts and review of the literature. Neuro Oncol 2002; 4: 278–299.
Canoll P, Goldman JE . The interface between glial progenitors and gliomas. Acta Neuropathol 2008; 116: 465–477.
Louis DN . Molecular pathology of malignant gliomas. Annu Rev Pathol 2006; 1: 97–117.
Hess CF, Schaaf JC, Kortmann RD, Schabet M, Bamberg M . Malignant glioma: patterns of failure following individually tailored limited volume irradiation. Radiother Oncol 1994; 30: 146–149.
Bowers WJ, Olschowka JA, Federoff HJ . Immune responses to replication-defective HSV-1 type vectors within the CNS: implications for gene therapy. Gene Ther 2003; 10: 941–945.
Harrow S, Papanastassiou V, Harland J, Mabbs R, Petty R, Fraser M et al. HSV1716 injection into the brain adjacent to tumour following surgical resection of high-grade glioma: safety data and long-term survival. Gene Ther 2004; 11: 1648–1658.
Markert JM, Medlock MD, Rabkin SD, Gillespie GY, Todo T, Hunter WD et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther 2000; 7: 867–874.
Papanastassiou V, Rampling R, Fraser M, Petty R, Hadley D, Nicoll J et al. The potential for efficacy of the modified (ICP 34.5(−)) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study. Gene Ther 2002; 9: 398–406.
Rampling R, Cruickshank G, Papanastassiou V, Nicoll J, Hadley D, Brennan D et al. Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma. Gene Ther 2000; 7: 859–866.
He B, Gross M, Roizman B . The gamma(1)34.5 protein of herpes simplex virus 1 complexes with protein phosphatase 1alpha to dephosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase. Proc Natl Acad Sci USA 1997; 94: 843–848.
Shah AC, Benos D, Gillespie GY, Markert JM . Oncolytic viruses: clinical applications as vectors for the treatment of malignant gliomas. J Neurooncol 2003; 65: 203–226.
Dempsey MF, Wyper D, Owens J, Pimlott S, Papanastassiou V, Patterson J et al. Assessment of 123I-FIAU imaging of herpes simplex viral gene expression in the treatment of glioma. Nucl Med Commun 2006; 27: 611–617.
World Health Organisation, 2007. http://www.who.int.
Morrison PF, Laske DW, Bobo H, Oldfield EH, Dedrick RL . High-flow microinfusion: tissue penetration and pharmacodynamics. Am J Physiol 1994; 266 (Part 2): R292–R305.
Jacobs A, Breakefield XO, Fraefel C . HSV-1-based vectors for gene therapy of neurological diseases and brain tumors: part II. Vector systems and applications. Neoplasia 1999; 1: 402–416.
Thorne RG, Nicholson C . In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. Proc Natl Acad Sci USA 2006; 103: 5567–5572.
Berges BK, Wolfe JH, Fraser NW . Stable levels of long-term transgene expression driven by the latency-associated transcript promoter in a herpes simplex virus type 1 vector. Mol Ther 2005; 12: 1111–1119.
Pike L, Petravicz J, Wang S . Bioluminescence imaging after HSV amplicon vector delivery into brain. J Gene Med 2006; 8: 804–813.
Suzuki M, Chiocca EA, Saeki Y . Stable transgene expression from HSV amplicon vectors in the brain: potential involvement of immunoregulatory signals. Mol Ther 2008; 16: 1727–1736.
Corso TD, Torres G, Goulah C, Roy I, Gambino AS, Nayda J et al. Assessment of viral and non-viral gene transfer into adult rat brains using HSV-1, calcium phosphate and PEI-based methods. Folia Morphol (Warsz) 2005; 64: 130–144.
Martins I, Pinto M, Wilson SP, Lima D, Tavares I . Dynamic of migration of HSV-1 from a medullary pronociceptive centre: antinociception by overexpression of the preproenkephalin transgene. Eur J Neurosci 2008; 28: 2075–2083.
McMenamin MM, Byrnes AP, Pike FG, Charlton HM, Coffin RS, Latchman DS et al. Potential and limitations of a gamma 34.5 mutant of herpes simplex 1 as a gene therapy vector in the CNS. Gene Ther 1998; 5: 594–604.
Oligino T, Poliani PL, Wang Y, Tsai SY, O′Malley BW, Fink DJ et al. Drug inducible transgene expression in brain using a herpes simplex virus vector. Gene Ther 1998; 5: 491–496.
Scarpini CG, May J, Lachmann RH, Preston CM, Dunnett SB, Torres EM et al. Latency associated promoter transgene expression in the central nervous system after stereotaxic delivery of replication-defective HSV-1-based vectors. Gene Ther 2001; 8: 1057–1071.
Szentistvanyi I, Patlak CS, Ellis RA, Cserr HF . Drainage of interstitial fluid from different regions of rat brain. Am J Physiol 1984; 246 (Part 2): F835–F844.
Wang S, Di S, Young WB, Jacobson C, Link Jr CJ . A novel herpesvirus amplicon system for in vivo gene delivery. Gene Ther 1997; 4: 1132–1141.
Howard MK, Kershaw T, Gibb B, Storey N, MacLean AR, Zeng BY et al. High efficiency gene transfer to the central nervous system of rodents and primates using herpes virus vectors lacking functional ICP27 and ICP34.5. Gene Ther 1998; 5: 1137–1147.
Wolfe D, Niranjan A, Trichel A, Wiley C, Ozuer A, Kanal E et al. Safety and biodistribution studies of an HSV multigene vector following intracranial delivery to non-human primates. Gene Ther 2004; 11: 1675–1684.
Hellums EK, Markert JM, Parker JN, He B, Perbal B, Roizman B et al. Increased efficacy of an interleukin-12-secreting herpes simplex virus in a syngeneic intracranial murine glioma model. Neuro Oncol 2005; 7: 213–224.
Kramm CM, Chase M, Herrlinger U, Jacobs A, Pechan PA, Rainov NG et al. Therapeutic efficiency and safety of a second-generation replication-conditional HSV1 vector for brain tumor gene therapy. Hum Gene Ther 1997; 8: 2057–2068.
Moriuchi S, Glorioso JC, Maruno M, Izumoto S, Wolfe D, Huang S et al. Combination gene therapy for glioblastoma involving herpes simplex virus vector-mediated codelivery of mutant IkappaBalpha and HSV thymidine kinase. Cancer Gene Ther 2005; 12: 487–496.
Moriuchi S, Krisky DM, Marconi PC, Tamura M, Shimizu K, Yoshimine T et al. HSV vector cytotoxicity is inversely correlated with effective TK/GCV suicide gene therapy of rat gliosarcoma. Gene Ther 2000; 7: 1483–1490.
Niranjan A, Moriuchi S, Lunsford LD, Kondziolka D, Flickinger JC, Fellows W et al. Effective treatment of experimental glioblastoma by HSV vector-mediated TNF alpha and HSV-tk gene transfer in combination with radiosurgery and ganciclovir administration. Mol Ther 2000; 2: 114–120.
Saydam O, Saydam N, Glauser DL, Pruschy M, Dinh-Van V, Hilbe M et al. HSV-1 amplicon-mediated post-transcriptional inhibition of Rad51 sensitizes human glioma cells to ionizing radiation. Gene Ther 2007; 14: 1143–1151.
Schellingerhout D, Rainov NG, Breakefield XO, Weissleder R . Quantitation of HSV mass distribution in a rodent brain tumor model. Gene Ther 2000; 7: 1648–1655.
Berges BK, Yellayi S, Karolewski BA, Miselis RR, Wolfe JH, Fraser NW . Widespread correction of lysosomal storage in the mucopolysaccharidosis type VII mouse brain with a herpes simplex virus type 1 vector expressing beta-glucuronidase. Mol Ther 2006; 13: 859–869.
Martino S, Marconi P, Tancini B, Dolcetta D, De Angelis MG, Montanucci P et al. A direct gene transfer strategy via brain internal capsule reverses the biochemical defect in Tay-Sachs disease. Hum Mol Genet 2005; 14: 2113–2123.
Natsume A, Mata M, Goss J, Huang S, Wolfe D, Oligino T et al. Bcl-2 and GDNF delivered by HSV-mediated gene transfer act additively to protect dopaminergic neurons from 6-OHDA-induced degeneration. Exp Neurol 2001; 169: 231–238.
Sun M, Kong L, Wang X, Lu XG, Gao Q, Geller AI . Comparison of the capability of GDNF, BDNF, or both, to protect nigrostriatal neurons in a rat model of Parkinson's disease. Brain Res 2005; 1052: 119–129.
Hadjipanayis CG, Fellows-Mayle W, Deluca NA . Therapeutic efficacy of a herpes simplex virus with radiation or temozolomide for intracranial glioblastoma after convection-enhanced delivery. Mol Ther 2008; 16: 1783–1788.
Matsumoto H, Kumon Y, Watanabe H, Ohnishi T, Shudou M, Li C et al. Antibodies to CD11b, CD68, and lectin label neutrophils rather than microglia in traumatic and ischemic brain lesions. J Neurosci Res 2007; 85: 994–1009.
Shieh MT, WuDunn D, Montgomery RI, Esko JD, Spear PG . Cell surface receptors for herpes simplex virus are heparan sulfate proteoglycans. J Cell Biol 1992; 116: 1273–1281.
WuDunn D, Spear PG . Initial interaction of herpes simplex virus with cells is binding to heparan sulfate. J Virol 1989; 63: 52–58.
Nguyen JB, Sanchez-Pernaute R, Cunningham J, Bankiewicz KS . Convection-enhanced delivery of AAV-2 combined with heparin increases TK gene transfer in the rat brain. Neuroreport 2001; 12: 1961–1964.
Mastakov MY, Baer K, Kotin RM, During MJ . Recombinant adeno-associated virus serotypes 2- and 5-mediated gene transfer in the mammalian brain: quantitative analysis of heparin co-infusion. Mol Ther 2002; 5: 371–380.
Chen MY, Hoffer A, Morrison PF, Hamilton JF, Hughes J, Schlageter KS et al. Surface properties, more than size, limiting convective distribution of virus-sized particles and viruses in the central nervous system. J Neurosurg 2005; 103: 311–319.
MacKay JA, Deen DF, Szoka Jr FC . Distribution in brain of liposomes after convection enhanced delivery; modulation by particle charge, particle diameter, and presence of steric coating. Brain Res 2005; 1035: 139–153.
Neeves KB, Sawyer AJ, Foley CP, Saltzman WM, Olbricht WL . Dilation and degradation of the brain extracellular matrix enhances penetration of infused polymer nanoparticles. Brain Res 2007; 1180: 121–132.
Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH . Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA 1994; 91: 2076–2080.
Marmarou A, Takagi H, Shulman K . Biomechanics of brain edema and effects on local cerebral blood flow. Adv Neurol 1980; 28: 345–358.
Todo T, Rabkin SD, Sundaresan P, Wu A, Meehan KR, Herscowitz HB et al. Systemic antitumor immunity in experimental brain tumor therapy using a multimutated, replication-competent herpes simplex virus. Hum Gene Ther 1999; 10: 2741–2755.
McMahon EJ, Bailey SL, Miller SD . CNS dendritic cells: critical participants in CNS inflammation? Neurochem Int 2006; 49: 195–203.
Fiandaca MS, Varenika V, Eberling J, McKnight T, Bringas J, Pivirotto P et al. Real-time MR imaging of adeno-associated viral vector delivery to the primate brain. Neuroimage 2009; 47 (Suppl 2): T27–T35.
Szerlip NJ, Walbridge S, Yang L, Morrison PF, Degen JW, Jarrell ST et al. Real-time imaging of convection-enhanced delivery of viruses and virus-sized particles. J Neurosurg 2007; 107: 560–567.
Acknowledgements
We acknowledge the financial assistance of the MRC, the Cure Parkinson's Trust and the Friends of the Bristol Oncology and Haematology Centre. We also kindly acknowledge the support of Roy Harris for his engineering expertise. The HSV-1 viral vectors were kindly provided by Biovex, UK.
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White, E., Bienemann, A., Megraw, L. et al. Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery. Cancer Gene Ther 18, 358–369 (2011). https://doi.org/10.1038/cgt.2011.2
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DOI: https://doi.org/10.1038/cgt.2011.2
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