Gene therapy for meningioma: improved gene delivery with targeted adenoviruses

Clemens M F Dirven, Jacques Grill, Martine L M Lamfers, Paul Van der Valk, Angelique M Leonhart, Victor W Van Beusechem, Hidde J Haisma, Herbert M Pinedo, David T Curiel, W Peter Vandertop, Winald R Gerritsen

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

OBJECT: 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.

Original languageEnglish
Pages (from-to)441-9
Number of pages9
JournalJournal of Neurosurgery
Volume97
Issue number2
DOIs
Publication statusPublished - Aug 2002

Cite this

Dirven, Clemens M F ; Grill, Jacques ; Lamfers, Martine L M ; Van der Valk, Paul ; Leonhart, Angelique M ; Van Beusechem, Victor W ; Haisma, Hidde J ; Pinedo, Herbert M ; Curiel, David T ; Vandertop, W Peter ; Gerritsen, Winald R. / Gene therapy for meningioma : improved gene delivery with targeted adenoviruses. In: Journal of Neurosurgery. 2002 ; Vol. 97, No. 2. pp. 441-9.
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title = "Gene therapy for meningioma: improved gene delivery with targeted adenoviruses",
abstract = "OBJECT: 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.",
keywords = "Adenoviridae/genetics, Adult, Aged, Gene Targeting/methods, Gene Transfer Techniques, Genetic Therapy/methods, Genetic Vectors/genetics, Humans, In Vitro Techniques, Meningeal Neoplasms/genetics, Meningioma/genetics, Middle Aged, Spheroids, Cellular/pathology, Tumor Cells, Cultured/pathology",
author = "Dirven, {Clemens M F} and Jacques Grill and Lamfers, {Martine L M} and {Van der Valk}, Paul and Leonhart, {Angelique M} and {Van Beusechem}, {Victor W} and Haisma, {Hidde J} and Pinedo, {Herbert M} and Curiel, {David T} and Vandertop, {W Peter} and Gerritsen, {Winald R}",
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Dirven, CMF, Grill, J, Lamfers, MLM, Van der Valk, P, Leonhart, AM, Van Beusechem, VW, Haisma, HJ, Pinedo, HM, Curiel, DT, Vandertop, WP & Gerritsen, WR 2002, 'Gene therapy for meningioma: improved gene delivery with targeted adenoviruses' Journal of Neurosurgery, vol. 97, no. 2, pp. 441-9. https://doi.org/10.3171/jns.2002.97.2.0441

Gene therapy for meningioma : improved gene delivery with targeted adenoviruses. / Dirven, Clemens M F; Grill, Jacques; Lamfers, Martine L M; Van der Valk, Paul; Leonhart, Angelique M; Van Beusechem, Victor W; Haisma, Hidde J; Pinedo, Herbert M; Curiel, David T; Vandertop, W Peter; Gerritsen, Winald R.

In: Journal of Neurosurgery, Vol. 97, No. 2, 08.2002, p. 441-9.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Gene therapy for meningioma

T2 - improved gene delivery with targeted adenoviruses

AU - Dirven, Clemens M F

AU - Grill, Jacques

AU - Lamfers, Martine L M

AU - Van der Valk, Paul

AU - Leonhart, Angelique M

AU - Van Beusechem, Victor W

AU - Haisma, Hidde J

AU - Pinedo, Herbert M

AU - Curiel, David T

AU - Vandertop, W Peter

AU - Gerritsen, Winald R

PY - 2002/8

Y1 - 2002/8

N2 - OBJECT: 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.

AB - OBJECT: 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.

KW - Adenoviridae/genetics

KW - Adult

KW - Aged

KW - Gene Targeting/methods

KW - Gene Transfer Techniques

KW - Genetic Therapy/methods

KW - Genetic Vectors/genetics

KW - Humans

KW - In Vitro Techniques

KW - Meningeal Neoplasms/genetics

KW - Meningioma/genetics

KW - Middle Aged

KW - Spheroids, Cellular/pathology

KW - Tumor Cells, Cultured/pathology

U2 - 10.3171/jns.2002.97.2.0441

DO - 10.3171/jns.2002.97.2.0441

M3 - Article

VL - 97

SP - 441

EP - 449

JO - Journal of Neurosurgery

JF - Journal of Neurosurgery

SN - 0022-3085

IS - 2

ER -