In vivo transgene expression from an adenoviral vector is altered following a 6-OHDA lesion of the dopamine system.
We have investigated the in vivo dynamics of an adenovirus-based, LacZ expressing vector, RAd36, at different doses, when injected unilaterally into the corpus striatum of normal rats. We have further investigated the characteristics of this vector in the presence of a 6-OHDA lesion of the nigrostriatal pathway. The dopamine-depleting lesion had an effect on both the number and the distribution of cells transduced by the adenoviral vector. The lesioned side of the brain contained significantly greater numbers of beta-galactosidase positive cells than the unlesioned side at 3 days, 1 week and 4 weeks post-injection and the distribution of transduced cells was altered by the presence of a dopamine lesion. We conclude that the increased levels of transgene expression seen in the lesioned hemisphere are due to a change in the diffusion characteristics of the injected vector in the lesioned hemisphere. These results indicate that, when investigating the use of virus-based vectors, ultimately for use in gene therapies in the CNS, the in vivo dynamics of the vector need to be assessed not only in the normal brain, but also in the pathological brain state such as animal models of target diseases.
Torres
E M
EM
Department of Biosciences, Cardiff University Museum Avenue, PO Box 911 Cardiff CF10 3US, UK. toresem@cf.ac.uk
Monville
C
C
Lowenstein
P R
PR
Castro
M G
MG
Dunnett
S B
SB
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000235:genetics*; D017930:Genes, Reporter / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics* / Q000627:therapeutic use; D007763:Lac Operon / Q000235:genetics; D009434:Neural Pathways / Q000378:metabolism / Q000503:physiopathology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism / Q000503:physiopathology; D013565:Sympatholytics; D014162:Transfection / Q000379:methods; D019076:Transgenes / Q000235:genetics*
D013565:Sympatholytics; D016627:Oxidopamine; D004298:Dopamine