Journal
HUMAN GENE THERAPY
Volume 18, Issue 2, Pages 118-129Publisher
MARY ANN LIEBERT INC
DOI: 10.1089/hum.2006.146
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Funding
- NINDS NIH HHS [K08 NS046430] Funding Source: Medline
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Transduction of malignant glioma with adenovirus serotype 5 (Ad5) vectors is limited by the low levels of coxsackievirus and adenovirus receptor (CAR) on tumor cells. However, malignant brain tumors have been found to overexpress a glioma-associated receptor, interleukin-13 receptor alpha 2 chain (IL-13R alpha 2), a marker of both glial transformation and tumor grade. To selectively target Ad5 to IL-13R alpha 2, we constructed a replication-deficient adenoviral vector that possesses an IL-13 ligand presented by a T4 phage fibritin shaft, and designated the new virus LU-13. Western blot and sequence analyses confirmed proper trimerization and ligand presentation by the T4 fibritin shaft. Confocal microscopy analysis of primary glioma suspensions incubated with viral recombinants showed that LU-13 colocalized with IL-13R alpha 2. Luciferase transduction assays conducted in both primary and passaged glioma cell cultures exhibited at least 10-fold enhanced gene transduction. Moreover, the virus preferentially bound to glioma cells, as documented by increased adenoviral E4 DNA copy number. In vitro competition assays performed with anti-human IL-13 monoclonal antibody confirmed significant attenuation of LU-13 transduction. These results were further confirmed in vivo, where LU-13 showed a 300-fold increase in transgene expression. In summary, we describe here the development of a novel and targeted adenoviral vector that binds IL-13R alpha 2. Our findings confirm the ability of LU-13 to bind IL13R alpha 2 and increase transgene expression, making it an attractive gene therapy vector for the treatment of malignant glioma in a clinical setting.
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