Gene Delivery Using Viral Vectors - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 233

formation and significant cell proliferation inhibition as well as induction of tumor
cell apoptosis [85] . Dumon et al. used AAV to deliver the tumor suppressor gene
fragile histidine triad (FHIT), which has shown slow tumor growth and long-term
survival in a mouse model, to human pancreatic cells [140] .
5.3.5.6 Combined Gene Therapy with AAV
Combination gene therapy can improve antitumor capacity. Transduction of
U-251SP human glioma cells in vitro with a bicistronic AAV vector containing
both the TK and human interleukin-2 genes (AAV-tk-IRES-IL2) rendered these
cells susceptible to GCV treatment and allowed the cells to produce IL-2 in a dose-
dependent manner; tumor volume was reduced by 35-fold compared to individual
therapy [141,142] .
5.3.5.7 Adeno-Associated Viral Vectors for Pancreatic Gene Delivery
Currently, available AAV is the most efficient at transducing nondividing cells.
Constructed recombinat AAV serotype 2 (AAV2LacZ), and pseudotyped AAV sero-
types 5 and 8 (AAV5LacZ, AAV8LacZ) carrying the LacZ reporter, showed that ade-
noviruses AAV2 and AAV8 are capable of transducing the pancreas in vivo , but with
different expression kinetics, efficiencies of transduction, and persistence [143] .
5.3.5.8 Anticonvulsant and Antiepileptogenic Effects Mediated by Adeno-
Associated Viral Vector Neuropeptide Y (NPY) Expression
Long-lasting NPY overexpression in the rat hippocampus with local application of
recombinant AAV vectors can significantly improve transgene expression in the treat-
ment of acute kainate seizures and kindling epileptogenesis. Serotype 2 AAV vector
increased NPY expression in hilar interneurons, whereas the chimeric serotype 1/2
vector caused far more widespread expression, including in mossy fibers, pyramidal
cells, and the subiculum. EEG seizures were reduced by 50-75%, depending on the
vector serotype, and seizure onset was markedly delayed. Targeted NPY gene transfer
can also provide a potential therapeutic principle for the treatment of drug-resistant
partial epilepsies. In rats injected with the chimeric serotype 1/2 vector, status epilep-
ticus was abolished [144] .
5.3.5.9 Adeno-Associated Viral Vector-Mediated Gene Therapy for Ischemia
For reduction of neuronal injury, AAV vectors are potentially useful for the delivery
of the gene to the CNS. This therapy can reduce ischemia-induced death [145] .
5.4 Retrovirus
Retroviruses are enveloped RNA viruses that are replicated in a host cell via the
enzyme reverse transcriptase (RT) to produce DNA from its RNA genome [146] . The