Ablation of tumor-derived stem cells transplanted to the central nervous system by genetic modification of embryonic stem cells with a suicide gene

Juyeon Jung, Neil R. Hackett, Robert G. Pergolizzi, Lorraine Pierre-Destine, Anja Krause, Ronald Crystal

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Embryonic stem cell (ESC)-based therapies open new possibilities as regenerative medicine for the treatment of human disease, but the presence of small numbers of undifferentiated ESCs within the transplant could lead to the development of tumors. The safety of ESC transplants would be enhanced if uncontrolled cell growth could be suppressed, using external stimuli. A lentiviral vector carrying the herpes simplex virus thymidine kinase (HSVtk) and green fluorescent protein (GFP) genes was used to genetically modify murine ESCs (HSVtk+GFP+ ESCs). In the presence of ganciclovir (GCV), 100% of HSVtk+GFP+ ESCs were killed in vitro, and 100% of flank tumors derived from HSVtk+GFP+ ESCs were eliminated. When CNS tumors were produced by the HSVtk+GFP + ESCs, the tumor mass was completely eliminated on GCV treatment for 1 week. After GCV treatment for 3 weeks, histologic analysis showed no residual tumor cells and TaqMan realtime polymerase chain reaction analysis showed no genomic HSVtk copies or HSVtk mRNA. These data demonstrate that it is possible to use ex vivo gene transfer to modify ESCs with conditional genetic elements that can be activated in vivo to control undifferentiated ESC outgrowth and to eliminate transduced ESCs that have escaped growth control after ESC-mediated therapy to the CNS.

Original languageEnglish
Pages (from-to)1182-1192
Number of pages11
JournalHuman Gene Therapy
Volume18
Issue number12
DOIs
Publication statusPublished - 1 Dec 2007
Externally publishedYes

Fingerprint

Neoplastic Stem Cells
Thymidine Kinase
Simplexvirus
Embryonic Stem Cells
Suicide
Central Nervous System
Green Fluorescent Proteins
Ganciclovir
Genes
Cell- and Tissue-Based Therapy
Neoplasms
Transplants
Regenerative Medicine
Residual Neoplasm
Growth
Therapeutics
Safety
Polymerase Chain Reaction
Messenger RNA

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Ablation of tumor-derived stem cells transplanted to the central nervous system by genetic modification of embryonic stem cells with a suicide gene. / Jung, Juyeon; Hackett, Neil R.; Pergolizzi, Robert G.; Pierre-Destine, Lorraine; Krause, Anja; Crystal, Ronald.

In: Human Gene Therapy, Vol. 18, No. 12, 01.12.2007, p. 1182-1192.

Research output: Contribution to journalArticle

Jung, Juyeon ; Hackett, Neil R. ; Pergolizzi, Robert G. ; Pierre-Destine, Lorraine ; Krause, Anja ; Crystal, Ronald. / Ablation of tumor-derived stem cells transplanted to the central nervous system by genetic modification of embryonic stem cells with a suicide gene. In: Human Gene Therapy. 2007 ; Vol. 18, No. 12. pp. 1182-1192.
@article{dc3391b99ec144f587fdd5fef128b9d1,
title = "Ablation of tumor-derived stem cells transplanted to the central nervous system by genetic modification of embryonic stem cells with a suicide gene",
abstract = "Embryonic stem cell (ESC)-based therapies open new possibilities as regenerative medicine for the treatment of human disease, but the presence of small numbers of undifferentiated ESCs within the transplant could lead to the development of tumors. The safety of ESC transplants would be enhanced if uncontrolled cell growth could be suppressed, using external stimuli. A lentiviral vector carrying the herpes simplex virus thymidine kinase (HSVtk) and green fluorescent protein (GFP) genes was used to genetically modify murine ESCs (HSVtk+GFP+ ESCs). In the presence of ganciclovir (GCV), 100{\%} of HSVtk+GFP+ ESCs were killed in vitro, and 100{\%} of flank tumors derived from HSVtk+GFP+ ESCs were eliminated. When CNS tumors were produced by the HSVtk+GFP + ESCs, the tumor mass was completely eliminated on GCV treatment for 1 week. After GCV treatment for 3 weeks, histologic analysis showed no residual tumor cells and TaqMan realtime polymerase chain reaction analysis showed no genomic HSVtk copies or HSVtk mRNA. These data demonstrate that it is possible to use ex vivo gene transfer to modify ESCs with conditional genetic elements that can be activated in vivo to control undifferentiated ESC outgrowth and to eliminate transduced ESCs that have escaped growth control after ESC-mediated therapy to the CNS.",
author = "Juyeon Jung and Hackett, {Neil R.} and Pergolizzi, {Robert G.} and Lorraine Pierre-Destine and Anja Krause and Ronald Crystal",
year = "2007",
month = "12",
day = "1",
doi = "10.1089/hum.2007.078",
language = "English",
volume = "18",
pages = "1182--1192",
journal = "Human Gene Therapy",
issn = "1043-0342",
publisher = "Mary Ann Liebert Inc.",
number = "12",

}

TY - JOUR

T1 - Ablation of tumor-derived stem cells transplanted to the central nervous system by genetic modification of embryonic stem cells with a suicide gene

AU - Jung, Juyeon

AU - Hackett, Neil R.

AU - Pergolizzi, Robert G.

AU - Pierre-Destine, Lorraine

AU - Krause, Anja

AU - Crystal, Ronald

PY - 2007/12/1

Y1 - 2007/12/1

N2 - Embryonic stem cell (ESC)-based therapies open new possibilities as regenerative medicine for the treatment of human disease, but the presence of small numbers of undifferentiated ESCs within the transplant could lead to the development of tumors. The safety of ESC transplants would be enhanced if uncontrolled cell growth could be suppressed, using external stimuli. A lentiviral vector carrying the herpes simplex virus thymidine kinase (HSVtk) and green fluorescent protein (GFP) genes was used to genetically modify murine ESCs (HSVtk+GFP+ ESCs). In the presence of ganciclovir (GCV), 100% of HSVtk+GFP+ ESCs were killed in vitro, and 100% of flank tumors derived from HSVtk+GFP+ ESCs were eliminated. When CNS tumors were produced by the HSVtk+GFP + ESCs, the tumor mass was completely eliminated on GCV treatment for 1 week. After GCV treatment for 3 weeks, histologic analysis showed no residual tumor cells and TaqMan realtime polymerase chain reaction analysis showed no genomic HSVtk copies or HSVtk mRNA. These data demonstrate that it is possible to use ex vivo gene transfer to modify ESCs with conditional genetic elements that can be activated in vivo to control undifferentiated ESC outgrowth and to eliminate transduced ESCs that have escaped growth control after ESC-mediated therapy to the CNS.

AB - Embryonic stem cell (ESC)-based therapies open new possibilities as regenerative medicine for the treatment of human disease, but the presence of small numbers of undifferentiated ESCs within the transplant could lead to the development of tumors. The safety of ESC transplants would be enhanced if uncontrolled cell growth could be suppressed, using external stimuli. A lentiviral vector carrying the herpes simplex virus thymidine kinase (HSVtk) and green fluorescent protein (GFP) genes was used to genetically modify murine ESCs (HSVtk+GFP+ ESCs). In the presence of ganciclovir (GCV), 100% of HSVtk+GFP+ ESCs were killed in vitro, and 100% of flank tumors derived from HSVtk+GFP+ ESCs were eliminated. When CNS tumors were produced by the HSVtk+GFP + ESCs, the tumor mass was completely eliminated on GCV treatment for 1 week. After GCV treatment for 3 weeks, histologic analysis showed no residual tumor cells and TaqMan realtime polymerase chain reaction analysis showed no genomic HSVtk copies or HSVtk mRNA. These data demonstrate that it is possible to use ex vivo gene transfer to modify ESCs with conditional genetic elements that can be activated in vivo to control undifferentiated ESC outgrowth and to eliminate transduced ESCs that have escaped growth control after ESC-mediated therapy to the CNS.

UR - http://www.scopus.com/inward/record.url?scp=37149040112&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=37149040112&partnerID=8YFLogxK

U2 - 10.1089/hum.2007.078

DO - 10.1089/hum.2007.078

M3 - Article

C2 - 18021021

AN - SCOPUS:37149040112

VL - 18

SP - 1182

EP - 1192

JO - Human Gene Therapy

JF - Human Gene Therapy

SN - 1043-0342

IS - 12

ER -