Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma

Adam M. Sonabend, Ilya V. Ulasov, Matthew A. Tyler, Angel A. Rivera, James M. Mathis, Maciej S. Lesniak

Research output: Contribution to journalArticle

166 Citations (Scopus)

Abstract

Gene therapy represents a promising treatment alternative for patients with malignant gliomas. Nevertheless, in the setting of these highly infiltrative tumors, transgene delivery remains a challenge. Indeed, viral vehicles tested in clinical trials often target only those tumor cells that are adjacent to the injection site. In this study, we examined the feasibility of using human mesenchymal stem cells (hMSC) to deliver a replication-competent oncolytic adenovirus (CRAd) in a model of intracranial malignant glioma. To do so, CRAds with a chimeric 5/3 fiber or RGD backbone with or without CXCR4 promoter driving E1A were examined with respect to replication and toxicity in hMSC, human astrocytes, and the human glioma cell line U87MG by quantitative polymerase chain reaction and membrane integrity assay. CRAd delivery by virus-loaded hMSC was then evaluated in vitro and in an in vivo model of mice bearing intracranial U87MG xenografts. Our results show that hMSC are effectively infected by CRAds that use the CXCR4 promoter. CRAd-CXCR4-RGD had the highest replication, followed by CRAd-CXCR4-5/3, in hMSC, with comparable levels of toxicity. In U87MG tumor cells, CRAd-CXCR4-5/3 showed the highest replication and toxicity. Virus-loaded hMSC effectively migrated in vitro and released CRAds that infected U87MG glioma cells. When injected away from the tumor site in vivo, hMSC migrated to the tumor and delivered 46-fold more viral copies than injection of CRAd-CXCR4-5/3 alone. Taken together, these results indicate that hMSC migrate and deliver CRAd to distant glioma cells. This delivery strategy should be explored further, as it could improve the outcome of oncolytic virotherapy for glioma.

Original languageEnglish
Pages (from-to)831-841
Number of pages11
JournalStem Cells
Volume26
Issue number3
DOIs
StatePublished - 1 Mar 2008

Fingerprint

Mesenchymal Stromal Cells
Adenoviridae
Glioma
Neoplasms
Oncolytic Virotherapy
Viruses
Injections
Transgenes
Heterografts
Astrocytes
Genetic Therapy
Clinical Trials
Cell Line
Polymerase Chain Reaction
Membranes

Keywords

  • Adenovirus
  • Gene therapy
  • Glioma
  • Migration
  • Oncolytic virus
  • Stem cells
  • Vector

Cite this

Sonabend, A. M., Ulasov, I. V., Tyler, M. A., Rivera, A. A., Mathis, J. M., & Lesniak, M. S. (2008). Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma. Stem Cells, 26(3), 831-841. https://doi.org/10.1634/stemcells.2007-0758
Sonabend, Adam M. ; Ulasov, Ilya V. ; Tyler, Matthew A. ; Rivera, Angel A. ; Mathis, James M. ; Lesniak, Maciej S. / Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma. In: Stem Cells. 2008 ; Vol. 26, No. 3. pp. 831-841.
@article{4451d25b669f407c8804a47e08a2d256,
title = "Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma",
abstract = "Gene therapy represents a promising treatment alternative for patients with malignant gliomas. Nevertheless, in the setting of these highly infiltrative tumors, transgene delivery remains a challenge. Indeed, viral vehicles tested in clinical trials often target only those tumor cells that are adjacent to the injection site. In this study, we examined the feasibility of using human mesenchymal stem cells (hMSC) to deliver a replication-competent oncolytic adenovirus (CRAd) in a model of intracranial malignant glioma. To do so, CRAds with a chimeric 5/3 fiber or RGD backbone with or without CXCR4 promoter driving E1A were examined with respect to replication and toxicity in hMSC, human astrocytes, and the human glioma cell line U87MG by quantitative polymerase chain reaction and membrane integrity assay. CRAd delivery by virus-loaded hMSC was then evaluated in vitro and in an in vivo model of mice bearing intracranial U87MG xenografts. Our results show that hMSC are effectively infected by CRAds that use the CXCR4 promoter. CRAd-CXCR4-RGD had the highest replication, followed by CRAd-CXCR4-5/3, in hMSC, with comparable levels of toxicity. In U87MG tumor cells, CRAd-CXCR4-5/3 showed the highest replication and toxicity. Virus-loaded hMSC effectively migrated in vitro and released CRAds that infected U87MG glioma cells. When injected away from the tumor site in vivo, hMSC migrated to the tumor and delivered 46-fold more viral copies than injection of CRAd-CXCR4-5/3 alone. Taken together, these results indicate that hMSC migrate and deliver CRAd to distant glioma cells. This delivery strategy should be explored further, as it could improve the outcome of oncolytic virotherapy for glioma.",
keywords = "Adenovirus, Gene therapy, Glioma, Migration, Oncolytic virus, Stem cells, Vector",
author = "Sonabend, {Adam M.} and Ulasov, {Ilya V.} and Tyler, {Matthew A.} and Rivera, {Angel A.} and Mathis, {James M.} and Lesniak, {Maciej S.}",
year = "2008",
month = "3",
day = "1",
doi = "10.1634/stemcells.2007-0758",
language = "English",
volume = "26",
pages = "831--841",
journal = "Stem Cells",
issn = "1066-5099",
publisher = "Wiley-Blackwell",
number = "3",

}

Sonabend, AM, Ulasov, IV, Tyler, MA, Rivera, AA, Mathis, JM & Lesniak, MS 2008, 'Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma', Stem Cells, vol. 26, no. 3, pp. 831-841. https://doi.org/10.1634/stemcells.2007-0758

Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma. / Sonabend, Adam M.; Ulasov, Ilya V.; Tyler, Matthew A.; Rivera, Angel A.; Mathis, James M.; Lesniak, Maciej S.

In: Stem Cells, Vol. 26, No. 3, 01.03.2008, p. 831-841.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma

AU - Sonabend, Adam M.

AU - Ulasov, Ilya V.

AU - Tyler, Matthew A.

AU - Rivera, Angel A.

AU - Mathis, James M.

AU - Lesniak, Maciej S.

PY - 2008/3/1

Y1 - 2008/3/1

N2 - Gene therapy represents a promising treatment alternative for patients with malignant gliomas. Nevertheless, in the setting of these highly infiltrative tumors, transgene delivery remains a challenge. Indeed, viral vehicles tested in clinical trials often target only those tumor cells that are adjacent to the injection site. In this study, we examined the feasibility of using human mesenchymal stem cells (hMSC) to deliver a replication-competent oncolytic adenovirus (CRAd) in a model of intracranial malignant glioma. To do so, CRAds with a chimeric 5/3 fiber or RGD backbone with or without CXCR4 promoter driving E1A were examined with respect to replication and toxicity in hMSC, human astrocytes, and the human glioma cell line U87MG by quantitative polymerase chain reaction and membrane integrity assay. CRAd delivery by virus-loaded hMSC was then evaluated in vitro and in an in vivo model of mice bearing intracranial U87MG xenografts. Our results show that hMSC are effectively infected by CRAds that use the CXCR4 promoter. CRAd-CXCR4-RGD had the highest replication, followed by CRAd-CXCR4-5/3, in hMSC, with comparable levels of toxicity. In U87MG tumor cells, CRAd-CXCR4-5/3 showed the highest replication and toxicity. Virus-loaded hMSC effectively migrated in vitro and released CRAds that infected U87MG glioma cells. When injected away from the tumor site in vivo, hMSC migrated to the tumor and delivered 46-fold more viral copies than injection of CRAd-CXCR4-5/3 alone. Taken together, these results indicate that hMSC migrate and deliver CRAd to distant glioma cells. This delivery strategy should be explored further, as it could improve the outcome of oncolytic virotherapy for glioma.

AB - Gene therapy represents a promising treatment alternative for patients with malignant gliomas. Nevertheless, in the setting of these highly infiltrative tumors, transgene delivery remains a challenge. Indeed, viral vehicles tested in clinical trials often target only those tumor cells that are adjacent to the injection site. In this study, we examined the feasibility of using human mesenchymal stem cells (hMSC) to deliver a replication-competent oncolytic adenovirus (CRAd) in a model of intracranial malignant glioma. To do so, CRAds with a chimeric 5/3 fiber or RGD backbone with or without CXCR4 promoter driving E1A were examined with respect to replication and toxicity in hMSC, human astrocytes, and the human glioma cell line U87MG by quantitative polymerase chain reaction and membrane integrity assay. CRAd delivery by virus-loaded hMSC was then evaluated in vitro and in an in vivo model of mice bearing intracranial U87MG xenografts. Our results show that hMSC are effectively infected by CRAds that use the CXCR4 promoter. CRAd-CXCR4-RGD had the highest replication, followed by CRAd-CXCR4-5/3, in hMSC, with comparable levels of toxicity. In U87MG tumor cells, CRAd-CXCR4-5/3 showed the highest replication and toxicity. Virus-loaded hMSC effectively migrated in vitro and released CRAds that infected U87MG glioma cells. When injected away from the tumor site in vivo, hMSC migrated to the tumor and delivered 46-fold more viral copies than injection of CRAd-CXCR4-5/3 alone. Taken together, these results indicate that hMSC migrate and deliver CRAd to distant glioma cells. This delivery strategy should be explored further, as it could improve the outcome of oncolytic virotherapy for glioma.

KW - Adenovirus

KW - Gene therapy

KW - Glioma

KW - Migration

KW - Oncolytic virus

KW - Stem cells

KW - Vector

UR - http://www.scopus.com/inward/record.url?scp=43049095411&partnerID=8YFLogxK

U2 - 10.1634/stemcells.2007-0758

DO - 10.1634/stemcells.2007-0758

M3 - Article

C2 - 18192232

AN - SCOPUS:43049095411

VL - 26

SP - 831

EP - 841

JO - Stem Cells

JF - Stem Cells

SN - 1066-5099

IS - 3

ER -