Elsevier

Progress in Neurobiology

Volume 55, Issue 4, 1 July 1998, Pages 399-432
Progress in Neurobiology

Viral vectors, tools for gene transfer in the nervous system

https://doi.org/10.1016/S0301-0082(98)00007-0Get rights and content

Abstract

Viral vectors are becoming increasingly important tools to investigate the function of neural proteins and to explore the feasibility of gene therapy to treat diseases of the nervous system. This gene transfer technology is based on the use of a virus as a gene delivery vehicle. In contrast to functional analysis of gene products in transgenic mouse, viral vectors can be applied to transfer genes to somatic, post-mitotic cells of fully developed animals. To date, five viral vector systems are available for gene transfer in the nervous system. These include recombinant and defective herpes viral vectors, adenoviral vectors, adeno-associated viral vectors and lentiviral vectors. Of these vectors herpes and adenoviral vectors are the most common in use. To date, one of the main hurdles in applying these two vector systems is the focal immune response that occurs following intraparenchymal infusion. Despite this limitation, herpes and adenoviral vectors have been used successfully to modify the physiological response to injury in several rodent models of neurodegeneration. The first purpose of this review is to describe the principles of the generation of viral vectors and to discuss the advantages and disadvantages of the viral vector systems currently in use for gene transfer in the nervous system. Secondly, we give an overview of the performance of these vectors following direct infusion in the nervous system and review the results obtained with these vectors in animal models of neurodegeneration and regeneration. The results of these initial studies have provided a framework for future experiments based on gene transfer strategies with viral vectors to study normal physiology and pathology of the nervous system.

Introduction

The possibility to deliver and express a foreign gene in somatic cells in vivo has for a long time been a dream of biological scientists. Gene transfer into postmitotic somatic cells would enable a direct analysis of the function and/or the therapeutic effect of a specific protein in an intact organism. In view of this the development of genetic intervention technology has attracted great interest not only as a means to resolve fundamental biological questions, but also as a focus of research toward somatic gene therapy of genetic diseases. The application of gene transfer is not limited to complement genetic, inherited disorders, but can also be used to augment existing or provide new functions to cells in the hope that this will be of therapeutic benefit.

The use of deoxynucleic acid (DNA) as a drug is simple in concept (Fig. 1). In practical terms, the delivery and expression of a therapeutic gene are dependent on efficient and safe vectors that carry the gene into the cell nucleus. Vectors are classified as viral and non-viral vectors. Viruses have evolved very efficient mechanisms to introduce their DNA into recipient cells. Therefore, viral vectors have been the obvious starting point in many experimental gene therapy protocols. A major challenge for the use of viral vectors is to solve the problem of the immunological rejection of transduced host cells. Non-viral vectors are based on cellular uptake of complexes between DNA and (bio)organic molecules. To date, the poor efficiency of gene transfer in vivo is a limitation of non-viral vectors. An advantage is that non-viral vectors are not or less immunogenic. If rendered more efficient non-viral vectors may provide a valuable alternative to viral vectors.

In the first part of this review an overview will be provided of the biology and vector technology of the four viruses that have so far been used as vectors to introduce foreign genes directly into the nervous system: herpes simplex virus (HSV), adenovirus (Ad), adeno-associated virus (AAV) and very recently, lentivirus. Although, shortcomings in all available vector systems have impeded the implementation of gene therapy, as we will show in the second part of this review several important observations in animal models have demonstrated the potential of viral vector mediated gene transfer in the nervous system.

Section snippets

Viral vector systems for the nervous system

The many potential experimental and therapeutic applications of in vivo gene delivery to the nervous system have resulted in an increasing effort in the development of systems to achieve this goal. The principles of the use of viral vectors for genetic manipulation of the nervous system is based on the following requirements that would make the vector suitable and safe as a gene transfer agent for neurons and glial cells: (1) The viral vector should be able to transduce non-dividing cells; (2)

Applications of viral vectors in the nervous system

The development of gene transfer techniques for the nervous system provides new opportunities to study the role of specific proteins in animal models of neurological diseases. The vector systems reviewed in the previous sections have been used to investigate the effects of viral vector-directed expression of tyrosine hydroxylase in an animal model for Parkinsons disease and of a range of neurotrophic factors in animal models of Alzheimer's disease and Parkinson's disease and motor neuron

Conclusions

The studies reviewed here have established a conceptual framework for genetic modification of the nervous system using viral vectors and have provided clues for the improvement of the currently available vector systems in the future. More specifically, the results obtained with the vectors encoding TH, neurotrophins, GDNF, CNTF, the glucose transporter, bcl-2, IL-1ra, axonin-1/TAG-1 and B-50/GAP-43 have demonstrated that it is possible to alter the functional performance of adult neurons in vivo

Acknowledgements

The authors acknowledge Gerard Boer and Paul Dijkhuizen for designing the computer images presented in this review. Furthermore, the authors thank Marc-Jan Ruitenberg for proofreading, and Ghislaine Meijer for checking the references included in this review.

References (336)

  • R Dash et al.

    A herpes simplex virus vector overexpressing the glucose transporter gene protects the rat dentate gyrus from an antimetabolite toxin

    Exp. Neurol.

    (1996)
  • B.L Davidson et al.

    Expression of Escherichia coli β-galactosidase and rat HPRT in the CNS of Macaca mulatta following adenoviral mediated gene transfer

    Exp. Neurol.

    (1994)
  • A.J Dekker et al.

    Grafting of nerve growth factor-producing fibroblasts reduces behavioral deficits in rats with lesions of the nucleus basalis magnocellularis

    Neurosci.

    (1994)
  • A.T Dobson et al.

    A latent, non-pathogenic HSV-1-derived vector stably expresses β-galactosidase in mouse neurons

    Neuron

    (1990)
  • K.J Fisher et al.

    Recombinant adenovirus deleted of all viral genes for gene therapy of cystic fibrosis

    Virology

    (1996)
  • L.J Fisher et al.

    Survival and function of intrastriatally grafted primary fibroblasts genetically modified to produce L-DOPA

    Neuron

    (1991)
  • P Aebischer et al.

    Transplantation in humans of encapsulated xenogeneic cells without immunosuppression

    Transplantation

    (1994)
  • P Aebischer et al.

    Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients

    Nature Med.

    (1996)
  • S Akli et al.

    Transfer of a foreign gene into the brain using adenovirus vectors

    Nat. Genet.

    (1993)
  • ALS CNTF Treatment Study Group (1996) A double-blind placebo-controlled clinical trial of subcutaneous recombinant...
  • J.K Andersen et al.

    Gene transfer into mammalian central nervous system using herpes virus vectors: Extended expression of bacterial LacZ in neurons using the neuron-specific enolase promoter

    Hum. Gene Ther.

    (1992)
  • J.K Anderson et al.

    Herpesvirus-mediated gene delivery into the rat brain: specificity and efficiency of the neuron-specific enolase promoter

    Cell. Mol. Neurobiol.

    (1993)
  • E Arenas et al.

    Neurotrophin-3 prevents the death of adult central noradrenergic neurons in vivo

    Nature

    (1994)
  • D Armentano et al.

    Characterization of an adenovirus gene transfer vector containing an E4 deletion

    Hum. Gene Ther.

    (1995)
  • D Armentano et al.

    Effect of the E4 region on the persistence of transgene expression from adenovirus vectors

    J. Virol.

    (1997)
  • R.W Atchison et al.

    Adenovirus-associated defective virus particles

    Science

    (1965)
  • L.E Babiss et al.

    Adenovirus type 5 early region 1b gene product is required for efficient shutoff of host protein synthesis

    J. Virol.

    (1984)
  • G Bajocchi et al.

    Direct in vivo gene transfer to ependymal cells in the central nervous system using recombinant adenovirus vectors

    Nat. Genet.

    (1993)
  • P Balan et al.

    An analysis of the in vitro and in vivo phenotypes of mutants of herpes simplex virus type I lacking glycoproteins gG, gE, gI or the putative gJ

    J. Gen. Virol.

    (1994)
  • D.S Battleman et al.

    HSV-1 vector-mediated gene transfer of the human nerve growth factor receptor p75hNGFR defines high-affinity NGF binding

    J. Neurosci.

    (1993)
  • B.J Baumgartner et al.

    Targeted transduction of CNS neurons with adenoviral vectors carrying neurotrophic factor genes confers neuroprotection that exceeds the transduced population

    J. Neurosci.

    (1997)
  • J Bennett et al.

    Adenovirus vector-mediated in vivo gene transfer into adult murine retina

    Invest. Opthal. Vis. Sci.

    (1994)
  • K.I Berns et al.

    Separation of two types of adeno-associated virus particles containing complementary polynucleotide chains

    J. Virol.

    (1972)
  • K.I Berns et al.

    Evidence for a single-stranded adeno-associated virus genome: isolation and separation of complementary single strands

    J. Virol.

    (1970)
  • A.L Betz et al.

    Attenuation of stroke size in rats using an adenoviral vector to induce overexpression of interleukin-1 receptor antagonist in brain

    J. Cereb. Blood Flow Metab.

    (1995)
  • S Biffo et al.

    B-50/GAP-43 expression correlates with process outgrowth in the embryonic mouse nervous system

    Eur. J. Neurosci.

    (1990)
  • A Bilang-Bleuel et al.

    Intrastriatal injection of an adenoviral vector expressing glial-cell-line-derived neurotrophic factor prevents dopaminergic neuron degeneration and behavioral impairment in a rat model of Parkinson disease

    Proc. Natl. Acad. Sci. USA

    (1997)
  • U Blömer et al.

    Highly efficient and sustained gene transfer in adult neurons with lentivirus vector

    J. Virol.

    (1997)
  • D.C Bloom et al.

    Neuron-specific restriction of a herpes simplex virus recombinant maps to the UL5 gene

    J. Virol.

    (1995)
  • E Bridge et al.

    redundant control of adenovirus late expression by early region 4

    J. Virol.

    (1989)
  • E Bridge et al.

    Interaction of adenoviral E4 and E1b products in late gene expression

    Virology

    (1990)
  • D.E Brough et al.

    A gene transfer vector-cell-line system for complete functional complementation of adenovirus early regions E1 and E4

    J. Virol.

    (1996)
  • A.I Brooks et al.

    Nerve growth factor somatic mosaicism produced by herpes virus directed expression of Cre recombinase

    Nat. Biotechnol.

    (1997)
  • Byrnes, A. P., MacLaren, R. E., and Charlton, H. M. (1996a). Immunological instability of persistent adenovirus vectors...
  • Byrnes, A. P., Wood, M. J. A., Charlton, H. M. (1996b). Role of T-cells in inflammation caused by adenovirus vectors in...
  • T Carlstedt

    Nerve fiber regeneration across the peripheral-central transitional zone

    J. Anat.

    (1997)
  • M Cayonette et al.

    Adenovirus-mediated gene transfer to retinal ganglion cells

    Invest. Ophthal. Vis. Sci.

    (1996)
  • L.S Chang et al.

    The adenovirus DNA binding protein can stimulate the rate of transcription directed by adenovirus and adeno-associated virus promoters

    J. Virol.

    (1990)
  • D.F Chen et al.

    Bcl-2 promotes regeneration of severed axons in mammalian CNS

    Nature

    (1997)
  • K.S Chen et al.

    Somatic gene transfer of NGF to the aged brain: behavioral and morphological amelioration

    J. Neurosci.

    (1995)
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