Diffuse encephaloventriculitis and substantial leukoencephalopathy after intraventricular administration of recombinant adenovirus.
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.
Tada
Tsuyoshi
T
Department of Neurosurgery, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan. tadatsu@hsp.md.shinshu-u.ac.jp
Nguyen
John Bang
JB
Hitoshi
Yasuyuki
Y
Watson
Nathan P
NP
Dunn
Jeffrey F
JF
Ohara
Shinji
S
Nagano
Satoshi
S
Kosai
Ken-Ichiro
K
Israel
Mark A
MA
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*
D004277:DNA, Single-Stranded; D005904:Glial Fibrillary Acidic Protein; D001616:beta-Galactosidase