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Chronic brain
inflammation and persistent herpes simplex virus 1 thymidine kinase expression
in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy:
Implications for clinical trials
R. A. Dewey5,
6, G. Morrissey1, 6, C.
M. Cowsill1, 6, D. Stone1,
F. Bolognani1, N.J.F. Dodd2,
T. D. Southgate1, D. Klatzmann3,
H. Lassmann4, M.G. Castro1
& P.R. Löwenstein1
1. Molecular
Medicine and Gene Therapy Unit, Room 1.302 Stopford Building, School of
Medicine,University of Manchester, Oxford Road, Manchester M13 9PT, UK.
2. Department of Medical Biophysics, Stopford Building, University of
Manchester, Oxford Road, Manchester M13 9PT, UK.
3. Laboratoire de Biologie et Therapeutique des Pathologies Immunitaires,
Universitè Pierre et Marie Curie, CNRS, Hôpital de la Pitiè-Salpétrière, 83
Boulevard de l'Hôpital, 75651, Paris Cedex 13, France.
4. Neurological Institute, University of Vienna, Schwarzspanierstrasse 17,
A-1090 Vienna, Austria.
5. R.A.D present address: Department of Neuropathology, Institute of Psychiatry,
Kings College London, DeCrespigny Park, Denmark Hill, London SE5 8AS, UK.
6. R.A.D., G.M. and C.M.C. contributed equally to this study.
Correspondence should be addressed to P R Löwenstein. e-mail: lowenstein@man.ac.uk
and M G Castro. e-mail: mcastro@fs1.scg.man.ac.ul
The long-term consequences of adenovirus-mediated conditional cytotoxic gene
therapy for gliomas remain uncharacterized.
We report here detection of active
brain inflammation 3 months after successful inhibition of syngeneic glioma
growth.
The inflammatory infiltrate consisted of activated macrophages/microglia
and astrocytes, and T lymphocytes positive for leucosyalin, CD3 and CD8, and
included secondary demyelination.
We detected strong widespread herpes simplex
virus 1 thymidine kinase immunoreactivity and vector genomes throughout large
areas of the brain.
Thus, patient evaluation and the design of clinical trials
in ongoing and future gene therapy for brain glioblastoma must address not only
tumor-killing efficiency, but also long-term active brain inflammation, loss of
myelin fibers and persistent transgene expression.
© 1999 Nature Publishing Group
Source: http://www.nature.com/cgi-taf/DynaPage.taf?file=/nm/journal/v5/n11/abs/nm1199_1256.html
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