Adenoviral vectors for in vivo gene delivery to oligodendrocytes: transgene expression and cytopathic consequences.
Replication defective viral vectors provide a potentially useful means of gene transfer to oligodendrocytes and thus for studying the pathogenesis of white matter disease. In this study we have examined the expression pattern of E1/E3 deleted adenoviral vectors expressing the reporter gene LacZ (AdlacZ) as a means of establishing the value of these vectors for gene delivery to oligodendrocytes in adult rat white matter. Our results indicate that although such an approach can be used to induce transgene expression in oligodendrocytes, it is complicated by both immunogenic and cytopathic effects. Thus, in normal animals, injection of DeltaE1/E3 adenoviral vectors was associated with a robust immune response that led to a lack of expression by 40 days after injection. In order to overcome this complication, virus was injected into the white matter of immuno-deficient athymic rats. These experiments indi- cated that even in the absence of a T cell response high viral titres of DeltaE1/E3 adenoviral vectors had a profound cytopathic effect leading to death of oligodendrocytes and hence demyelination. A similar cytopathic effect was demonstrated using an adenoviral vector expressing the neurocytokine ciliary neurotrophic factor (AdCNTF). As the titre of injected virus was decreased there was a significant decrease in the number of transgene expressing cells. These experiments therefore indicated that in immunodeficient recipients there is a narrow window of virus titre that results in a high rate of infectivity and expression without significant cytopathic consequences. At higher viral titres the cytopathic effects include oligodendrocyte death and demyelination, while at lower titres there is a significant decrease in the efficiency of the number of cells expressing the transgene.
Franklin
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Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
Quick
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Haase
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D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D003711:Demyelinating Diseases / Q000821:virology; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics*; D009836:Oligodendroglia / Q000276:immunology / Q000821:virology*; D051381:Rats; D011923:Rats, Nude; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013116:Spinal Cord / Q000276:immunology / Q000821:virology; D019076:Transgenes / Q000235:genetics*