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Inflammatory responses and their impact on β-galactosidase transgene expression following adenovirus vector delivery to the primate caudate nucleus

Gene Therapy volume 6, pages 1368–1379 (1999)Cite this article

Abstract

An E1, E3 deleted adenovirus vector, serotype 5, carrying the marker gene LacZ was bilaterally microinfused into the caudate nuclei of 10 St Kitts green monkeys. The location and number of cells expressing transgene and host immunologic response were evaluated at 1 week (n = 2) and 1 month (n = 8) following vector infusion. A large number of cells expressed β-galactosidase in some monkeys, exceeding 600000 in one monkey, but no expression was seen in three of 10. All monkeys had positive adenoviral antibody titers before vector infusion, indicating the possibility of previous exposure to some adenovirus, but only one showed a significant increase in titer afterwards. Inflammatory cell markers revealed an inverse correlation between transgene expression and the extent of inflammatory response. Dexamethasone administered immediately before and for 8 days following vector delivery, however, had no effect on transgene expression. The demonstration of significant inflammatory responses in the brain of some individual primates, including demyelination, indicates the need for new generations of adenovirus vectors, or the successful suppression of inflammatory responses, before this vector is suitable for non-cytotoxic clinical applications in the CNS.

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Acknowledgements

We thank R Jude Samulski, Gene Therapy Center, University of North Carolina-Chapel Hill, for his helpful advice and comments on the manuscript and Richard Flavell, Department of Immunobiology at Yale, for his suggestions and support of this project. We also thank Mr Richard Anderson and the University of Iowa Vector Core, the staff of the St Kitts Biomedical Research Foundation, St Kitts, West Indies, for assistance with the animal experiments and surgery, especially Sean O’Loughlin, John Wharton, Ernell Nisbett, Franklyn Connor, Ricaldo Pike and Wellington Sutton, and Mrs Ianina Filopovich and Mrs Irena Shavytsky for technical assistance. The study was primarily supported by USPHS Grants MH57958 and NS24032 and the Axion Research Foundation, and partial support by the Medical Research Institute Council of Children’s Memorial Hospital, Chicago (Dr Bohn), the Carver Foundation (partial support for Dr Davidson), and Research Scientist Award from NIMH MH00643 to Dr Redmond.

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Authors and Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, Neural Transplantation and Repair Program, New Haven, CT, USA

    M S Lawrence, J D Elsworth & D E Redmond Jr

  2. Department of Neurosurgery, Yale University School of Medicine, Neural Transplantation and Repair Program, New Haven, CT, USA

    M S Lawrence & D E Redmond Jr

  3. Department of Obstetrics and Gynecology, Yale University School of Medicine, Neural Transplantation and Repair Program, New Haven, CT, USA

    H G Foellmer & C Leranth

  4. Department of Pathology, Yale University School of Medicine, Neural Transplantation and Repair Program, New Haven, CT, USA

    J H Kim

  5. Department of Pediatrics, Children’s Memorial Institute for Education and Research, Northwestern University School of Medicine, Chicago, IL

    D A Kozlowski & M C Bohn

  6. Department of Immunobiology, Yale University School of Medicine, Neural Transplantation and Repair Program, New Haven, CT, USA

    A L M Bothwell

  7. Department of Medicine, University of Iowa College of Medicine, Iowa City, IA, USA

    B L Davidson

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  1. M S Lawrence
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Lawrence, M., Foellmer, H., Elsworth, J. et al. Inflammatory responses and their impact on β-galactosidase transgene expression following adenovirus vector delivery to the primate caudate nucleus. Gene Ther 6, 1368–1379 (1999). https://doi.org/10.1038/sj.gt.3300958

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