95
Views
1
CrossRef citations to date
0
Altmetric
Reviews

In vivo gene transfer to the CNS using recombinant SV40-derived vectors

, , &
Pages 1319-1335 | Published online: 11 Aug 2008

Bibliography

  • Betz AL, Shakui P, Davidson BL. Gene transfer to rodent brain with recombinant adenoviral vectors: effects of infusion parameters, infectious titer, and virus concentration on transduction volume. Exp Neurol 1998;150:136-42
  • Akli S, Caillaud C, Vigne E, et al. Transfer of a foreign gene into the brain using adenovirus vectors. Nat Genet 1993;3:224-8
  • Wu P, Phillips MI, Bui J, Terwilliger EF. Adeno-associated virus vector-mediated transgene integration into neurons and other nondividing cell targets. J Virol 1998;72:5919-26
  • Mccown TJ, Xiao X, Li J, et al. Differential and persistent expression patterns of CNS gene transfer by an adeno-associated virus (AAV) vector. Brain Res 1996;713:99-107
  • Naldini L, Blomer U, Gage FH, et al. Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proc Natl Acad Sci USA 1996;93:11382-8
  • Naldini L, Blomer U, Gallay P, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 1996;272:263-7
  • Mandel RJ, Rendahl KG, Spratt SK, et al. Characterization of intrastriatal recombinant adeno-associated virus-mediated gene transfer of human tyrosine hydroxylase and human GTP-cyclohydrolase I in a rat model of Parkinson's disease. J Neurosci 1998;18:4271-84
  • Watson DJ, Kobinger GP, Passini MA, et al. Targeted transduction patterns in the mouse brain by lentivirus vectors pseudotyped with VSVG, Ebola, Mokola, LCMV, or MuLV envelope proteins. Mol Ther 2002;5:528-37
  • Latchman DS, Coffin RS. Viral vectors for gene therapy in Parkinson's disease. Rev Neurosci 2001;12:69-78
  • Kordower JH, Emborg ME, Bloch J, et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science 2000;290:767-73
  • Bosch A, Perret E, Desmaris N, et al. Reversal of pathology in the entire brain of mucopolysaccharidosis type VII mice after lentivirus-mediated gene transfer. Hum Gene Ther 2000;11:1139-50
  • Daly TM, Vogler C, Levy B, et al. Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease. Proc Natl Acad Sci USA 1999;96:2296-300
  • Taylor RM, Wolfe JH. Decreased lysosomal storage in the adult MPS VII mouse brain in the vicinity of grafts of retroviral vector-corrected fibroblasts secreting high levels of β-glucuronidase. Nat Med 1997;3:771-4
  • Skorupa AF, Fisher KJ, Wilson JM, et al. Sustained production of β-glucuronidase from localized sites after AAV vector gene transfer results in widespread distribution of enzyme and reversal of lysosomal storage lesions in a large volume of brain in mucopolysaccharidosis VII mice. Exp Neurol 1999;160:17-27
  • Oh S, Pluhar GE, McNeil EA, et al. Efficacy of nonviral gene transfer in the canine brain. J Neurosurg 2007;107:136-44
  • Chu C, Zhang Y, Boado RJ, Partridge WM. Decline in exogenous gene expression in primate brain following intravenous administration is due to plasmid degradation. Phar Res 2006;23:1586-90
  • Huang RQ, Qu YH, Ke WL, et al. Efficient gene delivery targeted to the brain using a transferring-conjugated polyethyleneglycol-modified polyamidoamine dendrimer. FASEB J 2007;21:1117-25
  • Bharali DJ, Klejbor I, Stachowiak EK, et al. Organically modified silica nanoparticles: a nonviral vector for in vivo gene delivery and expression in the brain. Proc Natl Acad Sci USA 2005;102:11539-44
  • Yang Y, Haecker SE, Su Q, Wilson JM. Immunology of gene therapy with adenoviral vectors in mouse skeletal muscle. Hum Mol Genet 1996;5:1703-12
  • Yang Y, Su Q, Grewal IS, et al. Transient subversion of CD40 ligand function diminishes immune responses to adenovirus vectors in mouse liver and lung tissues. J Virol 1996;70:6370-7
  • Cao H, Koehler DR, Hu J. Adenoviral vectors for gene replacement therapy. Viral Immunol 2004;17:327-33
  • Kaplitt MG, Leone P, Samulski RJ, et al. Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Nat Genet 1994;8:148-54
  • Burger C, Gorbatyuk OS, Velardo MJ, et al. Recombinant AAV viral vectors pesudotyped with viral capsids from serotypes 1, 2, and 5 display differential efficiency and cell tropism after delivery to different regions of the central nervous system. Mol Ther 2004;10:302-17
  • Fu H, Muenzer J, Samulski RJ, et al. Self-complementary adeno-associated virus serotype 2 vector: global distribution and broad dispersion of AAV-mediated transgene expression in mouse brain. Mol Ther 2003;6:911-7
  • Passini MA, Wolfe JH. Widespread gene delivery and structure-specific patterns of expression in the brain after intraventricular injections of neonatal mice with an adeno-associated virus vector. J Virol 2001;75:12382-92
  • Davidson BL, Stein CS, Heth JA, et al. Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions in the mammalian central nervous system. Proc Natl Acad Sci USA 2000;97:3428-32
  • Miller DG, Adam MA, Miller AD. Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection. Mol Cell Biol 1990;10:4239-42
  • Blomer U, Naldini L, Kafri T, et al. Highly efficient and sustained gene transfer in adult neurons with a lentivirus vector. J Virol 1997;71:6641-9
  • Frampton AR Jr, Goins WF, Nakano K, et al. HSV trafficking and development of gene therapy vectors with applications in the nervous system. Gene Ther 2005;12:891-901
  • Strayer DS, Pomerantz RJ, Yu M, et al. Efficient gene transfer to hematopoietic progenitor cells using SV40-derived vectors. Gene Ther 2000;7:886-95
  • Strayer DS. SV40 as an effective gene transfer vector in vivo. J Biol Chem 1996;271:24741-6
  • Strayer DS, Kondo R, Milano J, Duan LX. Use of SV40-based vectors to transduce foreign genes to normal human peripheral blood mononuclear cells. Gene Ther 1997;4:219-25
  • Cordelier P, Calarota SA, Pomerantz RJ, et al. Inhibition of HIV-1 in the central nervous system by IFN-α2 delivered by an SV40 vector. J Interferon Cytokine Res 2003;23:477-88
  • Cordelier P, Van Bockstaele E, Calarota SA, Strayer DS. Inhibiting AIDS in the central nervous system: gene delivery to protect neurons from HIV. Mol Ther 2003;7:801-10
  • Cordelier P, Strayer D. Using gene delivery to protect HIV-susceptible CNS cells: inhibiting HIV replication in microglia. Virus Res 2006;118:87-97
  • Duan YY, Wu J, Zhu JL, et al. Gene therapy for human α1-antitrypsin deficiency in an animal model using SV40-derived vectors. Gastroenterology 2004;127:1222-32
  • Strayer DS, Milano J. SV40 mediates stable gene transfer in vivo. Gene Ther 1996;3:581-7
  • Strayer DS, Zern MA, Chowdhury JR. What can SV40-derived vectors do for gene therapy? Curr Opin Mol Ther 2002;4:313-23
  • Sauter BV, Parashar B, Chowdhury NR, et al. A replication-deficient rSV40 mediates liver-directed gene transfer and a long-term amelioration of jaundice in gunn rats. Gastroenterology 2000;119:1348-57
  • Louboutin JP, Reyes BAS, Agrawal L, et al. Strategies for CNS-directed gene delivery: in vivo gene transfer to the brain using SV40-derived vectors. Gene Ther 2007;14:939-49
  • Cordelier P, Morse B, Strayer DS. Targeting CCR5 with siRNAs: using recombinant SV40-derived vectors to protect macrophages and microglia from R5-tropic HIV. Oligonucleotides 2003;13:281-94
  • Desmaris N, Bosch A, Salaun C, et al. Production and neurotropism of lentivirus vectors pseudotyped with lyssavirus envelope glycoproteins. Mol Ther 2001;4:149-56
  • Mazarakis ND, Azzouz M, Rohll JB, et al. Rabies virus glycoprotein pseudotyping of lentiviral vectors enables retrograde axonal transport and access to the nervous system after peripheral delivery. Hum Mol Genet 2001;10:2109-21
  • Alisky JM, Hughes SM, Sauter SL, et al. Transduction of murine cerebellar neurons with recombinant FIV and AAV5 vectors. Neuroreport 2000;11:2669-73
  • Agrawal L, Louboutin JP, Reyes BAS, et al. Antioxidant enzyme gene delivery to protect from HIV-1 gp120-induced neuronal apoptosis. Gene Ther 2006;13:1645-56
  • Agrawal L, Louboutin JP, Strayer DS. Preventing HIV-1 Tat-induced neuronal apoptosis using antioxidant enzymes: mechanistic and therapeutic implications. Virology 2007;363:462-72
  • Burger C, Nguyen FN, Deng J, Mandel RJ. Systemic mannitol-induced hyperosmolarity amplifies rAAV2-mediated striatal transduction to a greater extent than local co-infusion. Mol Ther 2005;11:327-31
  • Ghodsi A, Stein C, Derksen T, et al. Systemic hyperosmolarity improves β-glucuronidase distribution and pathology in murine MPS VII brain following intraventricular gene transfer. Exp Neurol 1999;160:109-16
  • Mattson MP, Haughey NJ, Nath A. Cell death in HIV dementia. Cell Death Differ 2005;12:893-904
  • Major EO, Rausch D, Marra C, Clifford D. HIV-associated dementia. Science 2000;288:440-2
  • Mcarthur JC, Hoover DR, Bacellar H, et al. Dementia in AIDS patients: incidence and risk factors. Multicenter AIDS Cohort Study. Neurology 1993;43:2245-52
  • Koutsilieri E, Sopper S, Scheller C, et al. Parkinsonism in HIV dementia. J Neural Transm 2002;109:767-75
  • Ellis RJ, Deutsch R, Heaton RK, et al. Cognitive impairment is an independent risk factor for death in HIV infection. San Diego HIV Neurobehavioral Research Center Group. Arch Neurol 1997;54:416-24
  • Ances BM, Ellis RJ. Dementia and neurocognitive disorders due to HIV-1 infection. Semin Neurol 2007;27:86-92
  • Nath A, Sacktor N. Influence of highly active antiretroviral therapy on persistence of HIV in the central nervous system. Curr Opin Neurol 2006;19:358-61
  • Ranki A, Nyberg M, Ovod V, et al. Abundant expression of HIV Nef and Rev proteins in brain astrocytes in vivo is associated with dementia. AIDS 1995;9:1001-8
  • Van De Bovenkamp M, Nottet HS, Pereira CF. Interactions of human immunodeficiency virus-1 proteins with neurons: possible role in the development of human immunodeficiency virus-1 associated dementia. Eur J Clin Invest 2002;32:619-27
  • Cicala C, Arthos J, Rubbert A, et al. HIV-1 envelope induces activation of caspase-3 and cleavage of focal adhesion kinase in primary human CD4(+) T cells. Proc Natl Acad Sci USA 2000;97:1178-83
  • Twu C, Liu NQ, Popik W, et al. Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways. Proc Natl Acad Sci USA 2002;99:14386-91
  • Garden GA, Guo W, Jayadev S, et al. HIV associated neurodegeneration requires p53 in neurons and microglia. FASEB J 2004;18:1141-3
  • Xu Y, Kulkosky J, Acheampong E, et al. HIV-1-mediated apoptosis of neuronal cells: Proximal molecular mechanisms of HIV-1-induced encephalopathy. Proc Natl Acad Sci USA 2004;101:7070-5
  • Meucci O, Fatatis A, Simen AA, et al. Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity. Proc Natl Acad Sci USA 1998;95:14500-5
  • Regulier EG, Reiss K, Khalili K, et al. T-cell and neuronal apoptosis in HIV infection: implications for therapeutic intervention. Int Rev Immunol 2004;23:25-59
  • Kruman I, Nath A, Mattson MP. HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress. Exp Neurol 1998;154:276-88
  • Kaul M, Lipton SA. Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis. Proc Natl Acad Sci USA 1999;96:8212-6
  • Lipton SA, Choi YB, Pan ZH, et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 1993;364:626-32
  • Dreyer EB, Kaiser PK, Offermann JT, Lipton SA. HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. Science 1990;248:364-7
  • Lipton SA, Sucher NJ, Kaiser PK, Dreyer EB. Synergistic effects of HIV coat protein and NMDA receptor-mediated neurotoxicity. Neuron 1991;7:111-8
  • Ridet JL, Bensadoun JC, Deglon N, et al. Lentivirus-mediated expression of glutathione peroxidase: neuroprotection in murine models of Parkinson's disease. Neurobiol Dis 2006;21:29-34
  • Hoehn B, Yenari MA, Sapolsky RM, Steinberg GK. Glutathione peroxidase overexpression inhibits cytochrome C release and proapoptotic mediators to protect neurons from experimental stroke. Stroke 2003;34:2489-94
  • Watanabe Y, Chu Y, Andresen JJ, et al. Gene transfer of extracellular superoxide dismutase reduces cerebral vasospasm after subarachnoid hemorrhage. Stroke 2003;34:434-40
  • Louboutin JP, Agrawal L, Reyes BAS, et al. Protecting neurons from HIV-1 gp120-induced oxidant stress using both localized intracerebral and generalized intraventricular administration of antioxidant enzymes delivered by SV40-derived vectors. Gene Ther 2007;14:1650-61
  • Mastakov MY, Baer K, Xu R, et al. Combined injection of rAAV with mannitol enhances gene expression in the rat brain. Mol Ther 2001;3:225-32
  • Bourgoin C, Emiliani C, Kremer EJ, et al. Widespread distribution of β-hexosaminidase activity in the brain of a Sandhoff mouse model after coinjection of adenoviral vector and mannitol. Gene Ther 2003;10:1841-9
  • Doran SE, Ren XD, Betz AL, et al. Gene expression from recombinant viral vectors in the central nervous system after blood–brain barrier disruption. Neurosurgery 1995;36:965-70
  • Eriksson PS, Perfilieva E, Bjork-Eriksson T, et al. Neurogenesis in the adult human hippocampus. Nat Med 1998;4:1313-7
  • Thelle DP, Streit WJ. A chronicle of microglial ontogeny. Glia 1993;7:5-8
  • Mezey E, Chandross K, Harta G, et al. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 2000;290:1779-82
  • Cogle CR, Yachnis AT, Laywell ED, et al. Bone marrow transdifferentiation in brain after transplantation: a retrospective study. Lancet 2004;363:1432-7
  • Brazelton TR, Rossi FM, Keshet GI, Blau HM. From marrow to brain: expression of neuronal phenotypes in adult mice. Science 2000;290:1775-9
  • Eglitis MA, Mezey E. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci USA 1997;94:4080-5
  • Liu B, Daviau J, Nichols CN, Strayer DS. In vivo gene transfer into rat bone marrow progenitor cells using rSV40 viral vectors. Blood 2005;106:2655-62
  • Louboutin JP, Liu B, Reyes BAS, et al. Rat bone marrow progenitor cells transduced in situ by rSV40 vectors differentiate into multiple central nervous system lineages. Stem Cells 2006;24:2801-9
  • Weimann JM, Charlton CA, Brazelton TR, et al. Contribution of transplanted bone marrow cells to Purkinje neurons in human adult brains. Proc Natl Acad Sci USA 2003;100:2088-93
  • Weimann JM, Johansson CB, Trejo A, Blau HM. Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nat Cell Biol 2003;5:959-66
  • Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 2003;425:968-73
  • Sanchez-Ramos J, Song S, Cardozo-Pelaez F, et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 2000;164:247-56
  • Kopen GC, Prockop DJ, Phinney DG. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci USA 1999;96:10711-6
  • Scheffler B, Horn M, Blumcke I, et al. Marrow-mindedness: a perspective on neuropoiesis. Trends Neurosci 1999;22:348-57
  • Thomas LB, Gates MA, Steindler DA. Young neurons from the adult subependymal zone proliferate and migrate along an astrocyte, extracellular matrix-rich pathway. Glia 1996;17:1-14
  • Van Praag H, Schinder AF, Christie BR, et al. Functional neurogenesis in the adult hippocampus. Nature 2002;415:1030-4
  • Scharfman HE, Goodman JH, Sollas AL. Granule-like neurons at the hilar/CA3 border after status epilepticus and their synchrony with area CA3 pyramidal cells: functional implications of seizure-induced neurogenesis. J Neurosci 2000;20:6144-58
  • Jin K, Minami M, Lan JQ, et al. Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci USA 2001;98:4710-5
  • Magavi SS, Leavitt BR, Macklis JD. Induction of neurogenesis in the neocortex of adult mice. Nature 2000;405:951-5
  • Mezey E, Key S, Vogelsang G, et al. Transplanted bone marrow generates new neurons in human brains. Proc Natl Acad Sci USA 2003;100:1364-9
  • Tamaki S, Eckert K, He D, et al. Engrafment of sorted/expended human nervous system stem cells from fetal brain. J Neurosci Res 2002;69:976-86
  • Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 1997;276:71-4
  • Doetsch F, Caille I, Lim DA, et al. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 1999;97:703-16
  • Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 2000;425:479-94
  • Shors TJ, Miesegaes G, Beylin A, et al. Neurogenesis in the adult is involved in the formation of trace memories. Nature 2001;410:372-6
  • Ma Q, Jones D, Borghesani PR, et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci USA 1998;95:9448-53
  • Klein RS, Rubin JB, Gibson HD, et al. SDF-1 α induces chemotaxis and enhances sonic hedgehog-induced proliferation of cerebellar granule cells. Development 2001;128:1971-81
  • Hatch HM, Zheng D, Jorgensen ML, Petersen BE. SDF-1α/CXCR4: a mechanism for hepatic oval cell activation and bone marrow stem cell recruitment to the injured liver of rats. Cloning Stem Cells 2002;4:339-51
  • Steindler DA, Pincus DW. Stem cells and neuropoiesis in the adult human brain. Lancet 2002;359:1047-54
  • Lois C, Garcia-Verdugo JM, Alvarez-Buylla A. Chain migration of neuronal precursors. Science 1996;271:978-81
  • Zindy F, Cunningham JJ, Sherr CJ, et al. Postnatal neuronal proliferation in mice lacking Ink4d and Kip1 inhibitors of cyclin-dependent kinases. Proc Natl Acad Sci USA 1999;96:13462-7
  • Yang XW, Zhong R, Heintz N. Granule cell specification in the developing mouse brain as defined by expression of the zinc finger transcription factor RU49. Development 1996;122:555-66
  • Castro RF, Jackson KA, Goodell MA, et al. Failure of bone marrow cells to transdifferentiate into neural cells in vivo. Science 2002;297:1299
  • Wagers AJ, Sherwod RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic sem cells. Science 2002;297:2256-9
  • Yagi T, McMahon EJ, Takikita S, et al. Fate of hematopoietic cells in demyelinating mutant mouse, twitcher, following transplantation of GFP+ bone marrow cells. Neurobiol Dis 2004;16:98-109
  • Mezey E, Nagy A, Szalayova I, et al. Comments on: “Failure of bone marrow cells to transdifferentiate into neural cells in vivo”. Science 2003;299:1184
  • Strayer DS. Gene therapy using SV40-derived vectors: what does the future hold? J Cell Physiol 1999;181:375-84
  • Mckee HJ, Strayer DS. Immune responses against SIV envelope glycoprotein, using recombinant SV40 as a vaccine delivery vector. Vaccine 2002;20:3613-25
  • Pelkmans L, Kartenbeck J, Helenius A. Caveolar endocytosis of simian virus 40 reveals a new two-step vesicular-transport pathway to the E.R. Nature Cell Biol 2001;3:473-83
  • Pelkmans L, Puntener D, Helenius A. Local actin polymerization and dynamin recruitment in SV40-induced internalization of caveolae. Science 2002;296:535-9
  • Chen Y, Norkin LC. Extracellular simian virus 40 transmits a signal that promotes virus enclosure within caveolae. Exp Cell Res 1999;10:83-90
  • Yamada M, Kasamatsu H. Role of nuclear pore complex in simian virus 40 nuclear targeting. J Virol 1993;67:119-30
  • Anderson HA, Chen Y, Norkin LC. Bound simian virus 40 translocates to caveolin-enriched membrane domains, and its entry is inhibited by drugs that selectively disrupt caveolae. Mol Biol Cell 1996;7:1825-34
  • Dexter DT, Carter CJ, Wells FR, et al. Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease. J Neurochem 1987;52:381-9
  • Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial lateral sclerosis. Nature 1993;362:20-1
  • Beal MF. Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 1995;38:357-66
  • Smith MA, Perry G. Free radical damage, iron, and Alzheimer's disease. J Neurol Sci 1995;134:92-4
  • Smith MA, Sayre LM, Monnier VM, Perry G. Radical ageing in Alzheimer's disease. Trends Neurosci 1995;18:172-6
  • Cao W, Carney JM, Duchon A, et al. Oxygen free radicals involvement in ischemia and reperfusion of the brain injury to brain. Neurosci Lett 1998;88:233-8
  • Montoliu C, Valles S, Renau-Piqueras J, Guerri C. Ethanol-induced oxygen radical formation and lipid peroxidation in rat brain: effect of chronic alcohol consumption. J Neurochem 1994;63:1855-62
  • Smith CD, Carney JM, Starke-Reed PE, et al. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer's disease. Proc Natl Acad Sci USA 1991;88:10540-3

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.