Gene therapy for meningioma: improved gene delivery with targeted adenoviruses.
OBJECTIVE
Due to their surgical inaccessibility or aggressive behavior, some meningiomas cannot be cured with current treatment strategies. Gene therapy is an emerging strategy for the treatment of brain tumors, which the authors investigated to determine whether adenoviruses could be used for gene transfer in meningioma cells.


METHODS
The presence of the high-affinity Coxsackievirus and adenovirus receptor (CAR) for adenovirus type 5, as well as endothelial growth factor receptor (EGFR) and alpha, integrins (ITGAVs), were analyzed in primary tumors by using immunohistochemical studies and in primary meningioma cell cultures by using fluorescence-activated cell sorting. Targeting of adenoviruses to EGFR was achieved using bispecific antibodies, whereas targeting of adenoviruses to the ITGAVs was accomplished by insertion of an RGD (arginine-glycine-aspartic acid) motif in the adenovirus fiber H1 loop. Gene transfer efficiency of untargeted and targeted vectors was compared in primary cell cultures and in spheroids derived from patients' resected tumor material. The presence of CARs was observed in all tumors and in all but one of the derived primary meningioma cells. The higher expression of EGFRs and ITGAVs indicated that these receptors could be used as alternative targets to redirect the adenoviruses. Redirection of adenoviruses to the EGFRs or integrins enhanced gene transfer threefold (range two-sevenfold) for EGFRs in primary meningioma cells and ninefold (range three-23-fold) for integrins (p = 0.002, analysis of variance). The effect of adenovirus targeting was confirmed in spheroids composed of primary meningioma cells.


CONCLUSIONS
Gene transfer with adenoviruses targeted to tumor-specific receptors is very effective in primary meningioma cells and spheroids. These vectors are promising agents for gene therapy of meningiomas.
Department of Neurosurgery, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. c.dirven@vumc.nl
Clemens M F
CM
Dirven
Jacques
J
Grill
Martine L M
ML
Lamfers
Paul
P
Van der Valk
Angelique M
AM
Leonhart
Victor W
VW
Van Beusechem
Hidde J
HJ
Haisma
Herbert M
HM
Pinedo
David T
DT
Curiel
W Peter
WP
Vandertop
Winald R
WR
Gerritsen
D000256:Adenoviridae / Q000235:genetics*; D000328:Adult; D000368:Aged; D018390:Gene Targeting / Q000379:methods*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D066298:In Vitro Techniques; D008577:Meningeal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D008579:Meningioma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D018874:Spheroids, Cellular / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000473:pathology