Karl V. Clemons
Santa Clara Medical Center, San Jose
Perparim Kamberi
Department of Medicine, Division of infactious Disease and Geographic Medicine, Standford University, Callifornia
Tom M. Chiller
Department of Medicine, Division of infactious Disease and Geographic Medicine, Standford University, Callifornia
Raymond A. Sobel
Standford University, Callifornia
Elmer Brummer
Department of Medicine, Division of infactious Disease and Geographic Medicine, Standford University, Callifornia
Jay Kolls
Louisiana State University, Louisiana
David A. Stevens
Department of Medicine, Division of infactious Disease and Geographic Medicine, Standford University, Callifornia
ABSTRACT
Systemically administered murine interferon-γ (IFN-γ) has a modest therapeutic effect in a murine model of cryptococcal meningo-encephalitis, and markedly potentiates conventional chemotherapy. Viral vector-mediated gene transfer is a new potential strategy for delivery of therapy to the central nervous system (CNS). To investigate whether levels of IFN-γ higher than those with systemic administration can be achievedin the CNS with intra-CNS therapy, we studied IFN-γ levels in CSF after gene therapy in normal mice with a non-replicating adenovirus vector containing the murine IFN-γ gene, comparing two routes of vector administration. Two doses, 107.3 or 108.3 virus/mouse given in 50 μL were compared. Mean (n = 5/group) IFN-γ levels in the CSF (by ELISA) after diluent, 107.3 or 108.3 viruses given intrathecally (IT) were 0, 13510, >30000 pg ml-1 on day 5, and 320, 5190, 20740 pg ml-1 on day 10, respectively. In contrast, after intracerebral (IC) injection, levels were 0, 700, 835 pg ml-1 on day 5, and 10, 160 and 2160 pg ml-1on day 10. Serum IFN-γ levels were lower: 17, 168, 1139 pg ml-1 on day 5 and 65, 159, 305 pg ml-1 on day 10 after IT, but were 166, 700, 4375 and 141, 46, 138 pg ml-1 on days 5 and 10, respectively after IC administration of virus. CSF leukocytosis was noted on day 5, only after virus; 1250 and 1375 WBC mm-3 after 107.3 and 108.3 virus given IT, and 0 and 417 after IC administration of virus; all had cleared by day 10. Mice given 108.3 virus became hypoactive by day 3, with some having ruffled fur and ataxia, especially after IT; after 108.3 virus given IC signs were less severe. Few given 107.3 virus exhibited clinical signs. By day 10, animals in IC group had recovered and those in the IT group had improved. Histopathology showed meningitis with mononuclear infiltration only after virus by either route. This was more consistent with 108.3 virus, and was more prevalent on day 10. Thus, we show very high IFN-γ concentrations in the CSF, which were greater after IT administration of vector than after IC administration (where presumably parenchymal levels are higher), using gene therapy. This was complicated however, by transient meningitis with the high virus dose. The route that might give therapeutic benefit against meningoencephalitis with a pathogen needs additional study.
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How to cite this article
Karl V. Clemons, Perparim Kamberi, Tom M. Chiller, Raymond A. Sobel, Elmer Brummer, Jay Kolls and David A. Stevens, 2005. Effects of Interferon-γ Gene Therapy in the Murine Central Nervous System and Concentrations in Cerebrospinal Fluid after Intrathecal or Intracerebral Administration. Biotechnology, 4: 11-18.
DOI: 10.3923/biotech.2005.11.18
URL: https://scialert.net/abstract/?doi=biotech.2005.11.18
DOI: 10.3923/biotech.2005.11.18
URL: https://scialert.net/abstract/?doi=biotech.2005.11.18
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