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Adenoviral vectors: prospects for gene delivery to the central nervous system

Gene Therapy volume 6, pages 1349–1350 (1999)Cite this article

In recent years, adenoviruses (Ads) have received considerable attention for use in gene therapy because of their relatively large cloning capacity, ease of genetic manipulation and growth, and their ability to transduce a wide range of tissue types containing both replicating and non-replicating cells. However, the initial enthusiasm over Ads has been tempered somewhat by their poor performance in both preclinical and clinical studies. First-generation Ad vectors, which are rendered replication-defective by deletion of E1, have proven generally to be inadequate for the long-term, stable transgene expression necessary for the correction of most genetic diseases. Many factors have been identified which can contribute to this poor performance, including: the use of foreign versus self transgenes; strong innate and inflammatory responses to the vector; acute and chronic toxicity; and generation of anti-Ad cytotoxic T-lymphocytes. It is likely that decay of transgene expression is due to a combination of several, or all, of these factors. However, expression from first-generation vectors has been shown to persist for long periods in immunodeficient animals suggesting that gene transfer to immune-privileged sites, such as the central nervous system (CNS), may have a greater potential for success.

In this issue, three studies address Ad-mediated transgene delivery to the CNS. In the articles by Franklin et al.1 and O’Leary and Charlton,2 first-generation Ads are used to deliver a marker protein (β-galactosidase, β-gal) to the white matter of rat spinal cords. Gene expression was relatively efficient, and β-gal could be detected in a variety of cell types including oligodendrocytes and astrocytes, in addition to ependymal cells and neurons of the grey matter. Unfortunately, in both studies Ad delivery was associated with substantial tissue damage, including evidence of demyelination, and necrosis. The degree of destruction appeared to correlate with the dose of Ad vector. Immunohistochemistry of the CNS tissue following Ad transduction revealed infiltrating cells expressing markers for molecules such as major histocompatibility complex I and II, complement receptor 3, leukocyte common antigen and OX-2, reflective of dendritic cells, and macrophage infiltration; however, many of these markers were also present following buffer treatment, demonstrating that mechanical perturbation of the tissue during delivery may have been responsible for at least some of the inflammatory response. None the less, the dose-dependent nature of Ad toxicity indicates that either gene expression from the Ad vector or some component of the virion was responsible for these effects. Interestingly, the Franklin et al. study demonstrated evidence of toxicity in athymic rats, suggesting that gene transfer to the CNS is limited by factors other than the adaptive immune response.

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Authors and Affiliations

  1. Centre for Molecular Medicine, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, Ontario, Canada

    Robin J Parks

  2. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, L8N 3Z5, Ontario, Canada

    Jonathan L Bramson

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Parks, R., Bramson, J. Adenoviral vectors: prospects for gene delivery to the central nervous system. Gene Ther 6, 1349–1350 (1999). https://doi.org/10.1038/sj.gt.3301013

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