Neuropathological consequences of delivering an adenoviral vector in the rat brain.
BACKGROUND
Adenoviruses have many advantages as vehicles for gene delivery to the central nervous system (CNS) and retrograde transport of vectors to axonally linked sites has been postulated as a method for targeting neurons in remote brain regions. To investigate optimisation of this we injected different doses of vector and have documented the neuropathological side effects.


METHODS
Increasing doses of a first-generation adenoviral vector, expressing the lacZ gene, were inoculated in the rat striatum and beta-galactosidase expression was examined at the primary and secondary sites. Subsequently, at the highest dose of vector, transgene expression, the inflammatory response, tyrosine hydroxylase (TH) expression and the rotational behaviour of animals were studied over time.


RESULTS
When a high dose of an adenoviral vector was delivered to the rat striatum, high levels of transgene expression were seen at 5 days in the injection site and in the substantia nigra. Smaller doses gave lower levels of expression with little expression detectable in the substantia nigra. At later time points, with the high dose, a marked reduction in transgene expression was detected and was accompanied by cytopathic damage, a strong inflammatory response and animal weight loss. This was associated with depletion in TH levels and abnormal motor behaviour in animals.


CONCLUSIONS
Neuropathological damage in the dopaminergic system, caused by high doses of adenoviral vectors, has not previously been documented. To minimise damage and prolong transgene expression, it is important that the dose of vectors to be delivered is carefully optimised.
McMenamin
M Mary
MM
Department of Human-Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK. mary.mcmenamin@anat.ox.ac.uk
Lantos
Tibor
T
Carter
Emma E
EE
Hamilton
Louise
L
Charlton
Harry M
HM
Gonzalez
S Charlotte
SC
Wood
Matthew J A
MJ
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001522:Behavior, Animal; D001835:Body Weight; D001921:Brain / Q000201:enzymology / Q000473:pathology* / Q000821:virology; D007150:Immunohistochemistry; D051381:Rats; D019076:Transgenes; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D014446:Tyrosine 3-Monooxygenase