title: Diffuse encephaloventriculitis and substantial leukoencephalopathy after intraventricular administration of recombinant adenovirus.
abstract: OBJECTIVE
  The use of recombinant adenovirus as a vehicle for gene transfer into ependymal cells is a potential therapeutic tool for the treatment of various neural disorders. However, gene transfer into the ependymal cells of the ventricular wall is associated with high-level expression of the transferred gene, which declines rapidly. The purpose of this study is to understand the cause of this early decline in gene expression.
  
  
  METHODS
  Different doses of adenovirus-expressing beta-galactosidase (Ad-beta-gal) were injected into the lateral brain ventricle of C57BL/6 mice, and the brains were observed histologically and with magnetic resonance (MR) imaging for a month.
  
  
  RESULTS
  Inoculation of the lateral ventricle with more than 1 x 10(8) viral particles (2.6 x 10(6) pfu) resulted in a rapid decline of beta -gal expression. MR imaging indicated gradual ventriculomegaly and histological analysis showed the loss of the ependymal cells from the ventricular wall, lymphocytes infiltration near the wall, degeneration of myelinated fibers and apoptosis in the external capsule. Reactive astrocytes proliferated in the external capsule 17 days following inoculation. To avoid this irreversible brain atrophy, the inoculated adenovirus should be reduced to less than 1 x 10(7) particles (2.6 x 10(5) pfu) in mice.
  
  
  CONCLUSIONS
  Our results indicate the presence of a unique and diffuse immune response of the brain; therefore, the clinical use of recombinant virus for intraventricular gene transfer must be carefully evaluated.
authors.affiliation: Department of Neurosurgery, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan. tadatsu@hsp.md.shinshu-u.ac.jp
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Tada
authors.forename: John Bang
authors.initials: JB
authors.lastname: Nguyen
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Hitoshi
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Watson
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Dunn
authors.forename: Shinji
authors.initials: S
authors.lastname: Ohara
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagano
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Kosai
authors.forename: Mark A
authors.initials: MA
authors.lastname: Israel
mesh_terms: D000256:Adenoviridae / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000821:virology; D004277:DNA, Single-Stranded / Q000378:metabolism; D015140:Dementia, Vascular / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D004660:Encephalitis / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007276:Injections, Intraventricular / Q000379:methods; D020547:Lateral Ventricles / Q000473:pathology / Q000821:virology; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D013194:Staining and Labeling / Q000379:methods; D013997:Time Factors; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism*
chemical_list: D004277:DNA, Single-Stranded; D005904:Glial Fibrillary Acidic Protein; D001616:beta-Galactosidase