CD46 represents a target for adenoviral gene therapy of malignant glioma.
Malignant gliomas remain refractory to adenovirus serotype 5 (Ad5) gene therapy because of the lack of the primary adenoviral receptor, the coxsackie-adenovirus receptor (CAR), on tumor cells. To bypass the dependence on CAR, we investigated the expression of adenovirus serotype 3 (Ad3) receptor, or CD46, on glioma cells. First, we analyzed the expression of CD46 by RT-PCR on primary and passaged glioma cells. We then performed immunofluorescence studies to examine protein expression of CAR and CD46 on the same tumor lines. Finally, we constructed a replication-defective Ad vector that binds to CD46 and contains a luciferase transgenic cassette in place of the deleted E1 region: Ad5/3 (containing tail/shaft domain of Ad5 and knob domain of Ad3). These vectors were analyzed in vitro and in vivo against malignant glioma and compared with wild-type Ad5 or control vector Ad3/5 (containing tail of Ad5, shaft of Ad3, and knob of Ad5). The chimeric vector Ad5/3 showed a significant increase in the transduction efficiency of glioma tumor cells. At the same time, blocking the CD46 receptor caused a 65% inhibition of adenoviral infection when using Ad5/3. Taken together, these results indicate that CD46 is overexpressed by malignant glioma. Retargeting to the Ad3 receptor enhances gene transfer and offers a novel target for gene therapy of malignant brain tumors.
Ulasov
Ilya V
IV
Division of Neurosurgery, University of Chicago, IL 60637, USA.
Tyler
Matthew A
MA
Zheng
Sophy
S
Han
Yu
Y
Lesniak
Maciej S
MS
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D020869:Gene Expression Profiling; D015316:Genetic Therapy; D005822:Genetic Vectors; D005910:Glioma / Q000628:therapy*; D006801:Humans; D051916:Membrane Cofactor Protein / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011991:Receptors, Virus / Q000235:genetics
C497857:CD46 protein, human; C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D051916:Membrane Cofactor Protein; D011991:Receptors, Virus