Viral vectors, tools for gene transfer in 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.
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